International Immunopharmacology

FGFR4 inhibition augments paclitaxel-induced cell death in ovarian cancer

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, which has a high mortality rate due to frequent tumor recurrence. The development of drug resistance against the first-line chemotherapeutic agent, such as paclitaxel/Taxol®, represents a critical reason. The mechanisms of paclitaxel resistance remain largely unknown, and druggable drivers which can be targeted to prevent or revert paclitaxel resistance also need to be identified. Phos-tag-based screens in cells treated with paclitaxel were used to identify key regulators involved in paclitaxel resistance, such as fibroblast growth factor receptor 4 (FGFR4). The functional role of FGFR4 in regulating paclitaxel resistance was further identified using apoptosis assays, which included the identification of apoptotic marker levels and activities. The involvement of FGFR4 downstream signaling pathways involved in paclitaxel resistance were identified through western blotting and quantitative PCR. Their roles in regulating paclitaxel resistance were also validated using apoptosis assays. Immunofluorescent staining was performed to identify the synergy of paclitaxel and FGFR4 inhibition. Functional in vitro and in vivo studies demonstrate that FGFR4 depletion suppresses ovarian cancer cell proliferation, migration, and tumor growth. Importantly, FGFR4 silencing or specific inhibition can sensitize ovarian cancer cells to paclitaxel, whereas FGFR4 overexpression confers paclitaxel resistance. Mechanistically, FGFR4 regulates paclitaxel sensitivity in EOC cells through modulating the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL) via MEK-ERK-RSK signaling pathway. The inhibition of Bcl-xL or MEK-ERK-RSK signaling can also enhance paclitaxel-stimulated cytotoxicity. These findings indicate that targeting FGFR4 can be a promising novel strategy to overcome paclitaxel resistance and improve the outcomes of EOC patients.

Development of an immune gene prognostic classifier for survival prediction and respond to immunocheckpoint inhibitor therapy/chemotherapy in endometrial cancer

Immunotherapy has provided a promising therapeutic strategy for endometrial cancer (EC). The present study aims to develop a prognostic classifier based on immune-related genes (IRGs) to stratify EC patients. A total of 15 prognosis-related IRGs were further filtrated by multivariate Cox regression: LTA, TMSB15A, S100A14, PLA2G2A, PDGFRA, CLDN4, CTF1, PRLH, PTN, SST, HTR3E, NRP1, RORA, THRA and CBLC. A prognostic signature was constructed to split EC patients into the high-risk and low-risk group with statistically different survival outcomes, indicating good potential for the prognostic signature in survival surveillance. Furthermore, five compounds with potential anti-tumor effects were selected, including ciclopirox, ikarugamycin, vincamine, mevalolactone, and thiamazole. The abundance of follicular helper T cells, regulatory T cells and M0 macrophages were significantly enhanced in the high-risk group while resting memory CD4+ T cells, gamma delta T cells, M2 macrophages and resting mast cells were markedly elevated in the low-risk group. Memory activated CD4+ T cells, CD8+ T cells and activated mast cells were three most correlative with riskscore. An immunophenoscore (IPS) analysis revealed that patients of the low-risk group had a higher IPS and more inclined to respond to immune checkpoint inhibitors. Mutation analysis showed that patients of the low-risk group represented more tumor mutation burden but low riskscore, thus getting better prognosis. Patients of the low-risk group were more sensitive for gemcitabine, bleomycin, vinblastine, vinorelbine and methotrexate by prediction. We constructed a potential prognostic model and might offer new insight on the identification of new immune-related biomarkers and target therapy in EC.

γ-Glutamyl cyclotransferase contributes to endometrial carcinoma malignant progression and upregulation of PD-L1 expression during activation of epithelial-mesenchymal transition

Recent increases in the incidence of endometrial carcinoma represent a significant risk to women's health. We found that γ-glutamyl cyclotransferase (GGCT) was significantly up-regulated in endometrial carcinoma tissues and cells, which suggested that it may be a potential target for treatment of endometrial carcinoma. Furthermore, the impact of GGCT on proliferation, migration, and invasion of endometrial carcinoma has been demonstrated in vitro and in vivo using GGCT silencing and overexpression techniques. In addition, the epithelial-mesenchymal transition (EMT) was significantly inhibited in response to GGCT knockdown, which indicated that GGCT may contribute endometrial carcinoma malignancy during activation of the EMT. We also found that GGCT regulated PD-L1 expression during EMT activation. Furthermore, co-culture of endometrial carcinoma cells with CD8

Therapeutic targeting of the HPV E7 oncoprotein: Current advances and emerging strategies

Cervical cancer is one of the most common malignancies among women, with persistent infection by high-risk human papillomavirus (HPV) types, particularly HPV16 and HPV18, being the primary etiological factor. The viral oncoproteins E6 and E7 play pivotal roles in carcinogenesis by inactivating the tumor suppressor proteins p53 and pRb, respectively. E7 has emerged as a promising therapeutic target due to its continuous expression in transformed cells and its essential role in maintaining the malignant phenotype. Recent advances in molecular biology and nanotechnology have led to the development of novel therapeutic strategies aimed at silencing or inhibiting E7, such as immunotherapy, RNA interference (RNAi), CRISPR/Cas9-based genome editing, and the use of natural bioactive compounds. Immunotherapeutic approaches aim to elicit specific cytotoxic T-cell responses against E7, whereas RNAi and CRISPR/Cas systems enable precise suppression or disruption of the E7 oncogene. As a result, it leads to the reactivate of p53 and pRb pathways, cell cycle arrest, and apoptosis. Additionally, the design of innovative delivery systems, such as liposomal nanoparticles, polymeric carriers, and viral vectors, has improved the efficiency and safety of therapeutic gene delivery. Collectively, these targeted approaches offer promising prospects for the treatment of HPV-related cancers. However, further optimization of delivery platforms and minimization of off-target effects are essential for the successful clinical translation of E7-targeted therapies in cervical cancer.

Benzyl isothiocyanate triggers apoptosis by initiating autophagy through the generation of ROS and modulating the MAPK and PI3K-AKT pathway in cervical cancer cells

Benzyl isothiocyanate (BITC), a bioactive compound derived from cruciferous vegetables, has demonstrated antitumor potential against cervical cancer; However, its underlying mechanisms remain obscure. Through in vitro and in vivo experiments, this study focuses on unraveling the mechanisms by which BITC inhibits cervical cancer cell proliferation, with a particular emphasis on the relationship between autophagy and apoptosis regulated by oxidative stress and the critical roles of signaling pathways such as MAPK/PI3K-AKT in this process. The findings reveal that BITC exhibits potent cytotoxicity toward cervical cancer HeLa cells, significantly suppressing HeLa colony formation and migration, and inducing apoptosis and reactive oxygen species (ROS) production. Treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly reduced the proportion of BITC-induced apoptotic cells and the expression of apoptosis-related proteins. Mechanistically, BITC activates the JNK and p38 MAPK pathways while inhibiting the ERK1/2 MAPK and PI3K-AKT axes. However, administration of a JNK inhibitor or ERK/PI3K agonists reversed the BITC-induced expression of autophagy-related protein Beclin 1 and apoptotic protein Cleaved Caspase-3. Additionally, the ROS scavenger N-acetylcysteine abrogated BITC-affected protein expression, including p-JNK, p-ERK, p-PI3K, Beclin 1, and Cleaved Caspase-3. In vivo studies showed that BITC significantly inhibited tumor growth, upregulating the expression of p-JNK, LC3BII/I, Beclin I, Cleaved PARP, and Bax, while downregulating p-ERK, p-AKT, and Bcl-2 proteins. Overall, BITC exerts anti-cervical cancer effects through ROS-driven redox disruption and lethal autophagy induction, modulating MAPK and PI3K-AKT pathways. This finding underscores the potential of BITC for the treatment of cervical cancer.

Multi-omics profiling reveals that targeting NEK3 synergizes with cuproptosis to promote M1 macrophage polarization in cervical cancer

Cervical cancer (CC) remains a significant clinical challenge, necessitating novel therapeutic strategies that target tumor cells and remodel the immunosuppressive microenvironment. Cuproptosis, a copper-dependent cell death process, may influence antitumor immunity, but its mechanisms remain unclear. This study examines how cuproptosis modulates macrophage polarization in cervical cancer, focusing on the kinase NEK3. We employed a multi-omics approach, combining RNA sequencing and proteomic profiling of CC cells treated with elesclomol and CU (ES + Cu) to induce cuproptosis. Functional validation was conducted through in vitro assays measuring cell viability, migration, invasion, ROS production, and mitochondrial membrane potential. The role of NEK3 was further elucidated using overexpression and knockdown models. Macrophage polarization was assessed using co-cultures, ELISA, and flow cytometry. Cuproptosis induction suppressed CC cell proliferation, migration, and invasion, accompanied by ROS accumulation and mitochondrial dysfunction. Multi-omics analyses revealed extensive reprogramming of cellular stress and proteostasis pathways. NEK3 was identified as a key suppressor of cuproptosis. While NEK3 overexpression inhibited cuproptosis, its knockdown enhanced sensitivity to this cell death pathway. Furthermore, NEK3 depletion in tumor cells promoted M1-like macrophage polarization via MAPK signaling and increased macrophage recruitment. In vivo, NEK3 knockdown synergized with cuproptosis induction, leading to significant tumor growth suppression and an increased M1/M2 macrophage ratio. Our findings establish NEK3 as a critical molecular link between cuproptosis and Antitumor immunity in cervical cancer. By regulating both cell death sensitivity and macrophage polarization, NEK3 represents a promising therapeutic target for synergizing with cuproptosis-inducing agents to achieve dual cytotoxic and immunomodulatory effects.

Shared chemoresistance genes in ESCC and cervical Cancer: Insights from pharmacogenomics and Mendelian randomization

Neoadjuvant chemotherapy, particularly the use of platinum-based compounds and taxanes, is pivotal in the treatment of epithelial-derived tumors, such as cervical cancer and esophageal squamous cell carcinoma (ESCC); however, resistance remains a significant challenge. Utilizing Mendelian randomization (MR) with pharmacogenomics offers a novel approach to understanding the genetic underpinnings of drug responses, thereby aiding in personalized treatment. Single-cell RNA sequencing (scRNA-seq) analysis revealed a shared cellular subpopulation of CD8 + T effector memory (CD8 + TEM) cells that are pivotal in mediating chemotherapy resistance in ESCC and cervical cancer. A two-sample approach was employed for MR using data from genome-wide association studies, focusing on single nucleotide polymorphisms (SNPs) linked to CD8 + TEM cell expression. The SNPs were carefully selected, and statistical models, including the Wald ratio and inverse variance weighted methods, were used for robust causal effect estimation. These were supplemented by MR-Egger and weighted median analyses to address pleiotropy and variant heterogeneity. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) and immunohistochemistry assays were used to verify the relationship between the gene and drug sensitivity. Increased proportion of CD8 + TEM cells were observed in resistant samples. MR identified IL32, SPOCK1, and TRBC2 as key genes associated with resistance to cisplatin, carboplatin, and paclitaxel, respectively. These findings were validated across various cohorts and underscored the role of CD8 + TEM cells in drug responsiveness. The results of the MTT and immunohistochemistry assays confirmed the MR findings. Our study highlights the significant role of CD8 + TEM cells in the chemoresistance of ESCC and cervical cancer and identified three genetic markers crucial for resistance to common chemotherapeutic agents. These findings suggest potential pathways for developing personalized treatment strategies, offering clinically relevant insights that could enhance therapeutic efficacy and help overcome drug resistance in patients with ESCC or cervical cancer.

USP34 regulates PIN1-cGAS-STING axis-dependent ferroptosis in cervical cancer via SUMOylation

Cervical cancer is a prevalent form of cancer in women, and the inhibition of ferroptosis has been shown to promote the progression of cervical cancer tumours. This study aimed to investigate the role of PIN1 in regulating ferroptosis in cervical cancer, focusing on its ability to modulate the cGAS-STING pathway and the potential involvement of USP34 as an upstream regulator of PIN1. PIN1-overexpressing and PIN1-knockdown cell lines were constructed. In addition to activating p-STING via PIN1 knockdown and inhibiting p-STING via PIN1 overexpression, cell activity was evaluated via CCK8, EdU, transwell and flow cytometry assays. The expression of USP34, PIN1, cGAS, p-STING, and STING was analysed through qRT-PCR and immunofluorescence. Western blot analysis was used to detect the regulatory effects of USP34, PIN1, cGAS, p-STING, and STING, as well as SUMOylation. Ferroptosis was detected by ROS immunofluorescence, the mitochondrial membrane potential, and mitochondrial electron microscopy. Furthermore, PIN1-knockdown cells were used to construct xenograft tumours in BALB/c male nude mice, and the relevant verification experiments were performed in vivo. PIN1 can increase the proliferation and invasion of cervical cancer cells by significantly inhibiting ferroptosis. The mechanism by which PIN1 promotes cancer is inhibition of the cGAS-STING pathway. Additionally, we found that USP34 could increase the expression of PIN1 via SUMOylation in cervical cancer cells. This study confirmed that USP34 could upregulate PIN1 expression and SUMOylation, thereby inhibiting ferroptosis by suppressing the cGAS-STING pathway and in turn promoting the progression of cervical cancer.

Thymoquinone enhances efficacy of cervical cancer therapeutic vaccines via modulating CD8+ T cells

Cervical cancer, primarily driven by persistent high-risk human papillomavirus (HPV) infection, remains a global health challenge. While therapeutic vaccines offer promising alternatives to conventional treatments, their clinical efficacy is often hindered by limitations in antigen presentation and the immunosuppressive tumor microenvironment (TME). In this study, we explore the potential of thymoquinone (TQ), a bioactive compound derived from Nigella sativa seeds, to enhance the efficacy of cervical cancer therapeutic vaccines. Utilizing a mouse cervical cancer xenograft model with TC-1 cells expressing HPV16 E6/E7 and ras genes, we observed substantial heterogeneity in vaccine-induced antitumor responses. Mice were stratified into hyporesponsiveness (Hypo) and hyperresponsiveness (Hyper) groups based on tumor progression. The Hyper group exhibited significantly reduced tumor growth, marked by increased CD4

Improved outcomes of palliative radiotherapy combined with immune checkpoint inhibitors in recurrent or metastatic cervical cancers

Immunotherapy provides a remarkable survival advantage for patients with recurrent or metastatic cervical cancer (R/M CC). However, the role of immunotherapy in combination with radiotherapy in R/M CC remains unclear. We retrospectively analyzed factors affecting immunotherapy effectiveness in patients with R/M CC. Clinical outcomes including tumor response and patient survival were assessed. Kaplan-Meier curves with the log-rank test were employed to compare survival data. Cox regression analysis was utilized to investigate prognostic factors. A total of 65 R/M CC patients treated with immune checkpoint inhibitors were eligible for analysis. We found that immunotherapy combined with palliative radiotherapy showed a significant positive correlation with complete response (OR = 6.31; 95 %CI: 1.74-22.91; p = 0.005). The 36-month progression-free survival (PFS) rate (73.7 % vs 33.8 %, p = 0.0048) and 36-month overall survival (OS) rate (85.7 % vs 38.7 %, p = 0.0043) were also prominently increased. We further demonstrated that patients prolonged 36-month PFS rate (69.9 % vs 15.2 %; p < 0.001) and 36-month OS rate (64.6 % vs 39.7 %; p = 0.032) when they had more than 4 cycles of immunotherapy. Meanwhile, our findings showed that patients with only recurrence had longer 36-month OS rate (77.7 % vs 44.4 % vs 40.1 %; p = 0.024) compared to those with only metastasis and both. We also observed that patients with squamous carcinoma had higher 2-year PFS rate (57.9 % vs 14.6 %; p = 0.042) than those with other pathological subtypes (adenocarcinoma, adenosquamous carcinoma and neuroendocrine carcinoma). The combination of immunotherapy and palliative radiotherapy increased complete response rates and improved survivals in recurrent or metastatic cervical cancer patients.

Transforming growth factor-β micro-environment mediated immune cell functions in cervical cancer

Propensity to develop cervical cancer (CC) in human papilloma virus (HPV) infected individual could potentially involve the impaired immune functioning. Several stages of HPV surveillance by immune cells in tumor micro-environment (TME) is regulated mainly by transforming growth factor-beta (TGF-β) and is crucial for the establishment of CC. The role of TGF-β in the initiation and progression of CC is very complex and involve different suppressor of mothers against decapentaplegic homolog (SMAD) dependent and SMAD independent signaling mechanism(s). This review summarizes the handling of HPV by immune cells such as T lymphocytes, B lymphocytes, natural killer cells (NK), dendritic cells (DC), monocytes, macrophages, myeloid derived suppressor cells (MDSC) and their regulation by TGF-β. The hijack mechanisms adapted by HPV to evade this surveillance process is discussed. Biomarkers indicating the stages of CC and immune checkpoints that can be targeted for improved outcome are included for immune-based theragnostics. This review also addresses the direct actions of TGF-β on CC cells and tumor/immune cell interactions. Therapies focused on targeting TGF-β using small molecule inhibitors, monoclonal antibodies and TGF-β chimeric antigen receptor (CAR)T cells are collated to understand the current strategies related to TGF-β in the management of CC.

The role of immune cells and inflammasomes in Modulating cytokine responses in HPV-Related cervical cancer

One of the most frequent cancers associated with gynecological malignancies is cervical cancer. Nearly 99% of cervical tumor lesions are produced by prolonged infection with hr-HPV and almost 70% of cases are related to HPV-16 and HPV-18. The human immune system has a crucial role in defending against infections caused by HPV infection. As an illustration, elevation in neutrophils reduces T cell antitumor activity, which in turn results in the development of malignancies and subsequently inhibits immune system function. HPV-infected cells, also, express a significant number of genes related to pro-inflammatory mediators including IL-1β. Moreover, inflammasomes, which are multi-protein complexes, owing the production of the pro-inflammatory cytokines including IL-1β and IL-18 in response to viral infections. In other words, these multi-protein complexes have a crucial role in tumor immunity regulation through the secretion of pro-inflammatory cytokines and induction of antigen presentation and maturation by APCs including dendritic cells. In this study, we attempted to investigate the inflammasome's general role in the initiation and advancement of cervical cancer, as well as a summary of the pathways connected to the possible participation of inflammasomes in the pathological process of cervical carcinoma and immune cell engagement. Novel strategy techniques that target the inflammatory reaction of tumor-related antigens may be created with an understanding of inflammasome-dependent pathways to accomplish tumor immunotherapy and cervical tumor treatment.

Classification of serous ovarian carcinoma based on immunogenomic profiling

Treatment of serous ovarian cancer (SOC) remains a clinical challenge. Classification of SOC based on immunogenomic profiling is important for establishing immunotherapy strategies. We extracted RNA-seq data of SOC from TCGA-OV. The samples were ultimately classified into high immune (Immunity_H) group and low immune (Immunity_L) group based on the immunogenomic profiling of 29 immune signatures by using unsupervised machine learning methods and modified by multifaceted characterization of immune response. High immune group showed the lower tumor purity and higher anti-tumor immune activity, and the higher expressions of PDCD1, CD274 and CTLA4. Furthermore, the overall survival time and the progression-free interval were significantly longer in high-immun group. The differentially expressed genes were mainly enriched in some immune response related functional terms and PI3K-AKT signaling pathway. According to ImmuCellAI, the abundance of various T cell subtypes in high immune group were significantly higher than those in low immune group. This novel immunotyping shows promise for prognostic and immunotherapeutic stratification in SOC patients.

SnapShot: TP53 status and macrophages infiltration in TCGA-analyzed tumors

The infiltration of immune cells is a hallmark of most forms of malignancy. It is well known that in Tumor Microenvironment (TME), monocytes undergo reprogramming process to differentiate into Tumor Associated Macrophages (TAMs) (M2 macrophages). Interestingly, this reprogramming process depends on signals provided by tumors. Hence, tumors from several tissues are infiltrated by functionally distinct TAMs populations. Tumor Protein p53(TP53) plays a role in the regulation or progression of DNA damage and repair through multiple mechanisms of the cell cycle, apoptosis, and genomic stability. Although, TP53 acts as a physiological break for M2 macrophages polarization; the potential regulatory function of TP53 in the infiltration of macrophages is still unknown. We used the Cancer Genomic Atlas (TCGA) clinical data from 10,009 samples across 30 types of cancer via the Tumor IMmune Estimation Tool (TIMER) (https://cistrome.shinyapps.io/timer/) to investigate whether TP53 status has an important clinical outcome on macrophages infiltration in different cancer types. Our analysis of TCGA showed that Ovarian Serous Cystadenocarcinoma (OV) patients with mutant TP53 had significantly higher macrophages infiltration than those with wild-type TP53 (P-value < 0.05) and poor prognosis associated. In contrast, Stomach Adenocarcinoma (STAD) patients with wild-type TP53 had considerably higher macrophages infiltration than those with mutant TP53 (P-value < 0.01) and poor clinical outcomes. Herein, our study sheds light on the novel clinical role of TP53 in macrophages infiltration in TME of OV and STAD patients. Furthermore, the modulation of TP53 and its co-regulators may serve as promising targets for OV and STAD patients.

Tumor associated macrophages in the molecular pathogenesis of ovarian cancer

The tumor microenvironment is a critical factor that enhances cancer progression, drug resistance, and failure of therapeutic approaches. Several cellular and non-cellular factors are involved in cancer promotion. Among the several cell populations in the tumor microenvironment, macrophages, as one of the most abundant innate immune cells within the tumor milieu, have attracted extensive attention among several researchers because of their critical role in innate pathophysiology of multiple disorders, as well as ovarian cancer. High plasticity and consequent high ability to adapt to environmental alternations by adjusting their cellular metabolism and immunological phenotype is the notable characteristic of macrophages. Therefore, the critical function of tumor-associated macrophages in ovarian cancer is highlighted in the growing body of recent studies. In this article, we will comprehensively focus on significant impacts of the macrophages on ovarian cancer progression, by discussing the role of macrophages as one of the fundamental immune cells present in tumor milieu, in metabolic reprogramming of transformed cells, and involvement of these cells in the ovarian cancer initiation, progression, invasion, and angiogenesis. Moreover, we will summarise recent studies evaluating the effects of targeting macrophages in ovarian cancer.

Fluzoparib disrupts Golgi apparatus to inhibit O-GlcNAcylation and nuclear translocation of β-catenin to attenuate ovarian cancer invasion and metastasis

Ovarian cancer is one of the most common malignant tumors of the female reproductive system, with the majority of patients already presenting with peritoneal dissemination and other metastases at the time of initial diagnosis. Fluzoparib (FZ) is the first domestically developed PARP inhibitor in China. The efficacy of FZ in inhibiting the invasiveness and metastasis of ovarian cancer remains uncertain, and its potential mechanisms are yet to be elucidated. O-GlcNAcylation is an important post-translational modification that is crucial for the function and localization of proteins, with the Golgi apparatus serving as an important subcellular compartment involved in O-GlcNAcylation-related protein regulation. However, the regulatory effects of FZ on the Golgi apparatus and O-GlcNAcylation remain unclear. Here, we found that FZ significantly reduces the viability, proliferative capacity, invasiveness, and metastatic potential of ovarian cancer cells while promoting apoptosis. In vivo, FZ decreases the formation of ascites in mice and diminishes peritoneal metastatic implantation without causing significant damage to major organs. Mechanistically, FZ disrupts the morphology and function of the Golgi apparatus, inhibits the O-GlcNAcylation of β-catenin, and promotes competitive phosphorylation of β-catenin, thereby preventing its translocation to the nucleus and ultimately inhibiting the invasion and metastasis of ovarian cancer. In summary, this study reveals that FZ disrupts the Golgi apparatus and inhibits the O-GlcNAcylation and nuclear translocation of β-catenin, thereby preventing the invasion and metastasis of ovarian cancer.

Caulerpin alleviates cyclophosphamide-induced ovarian toxicity by modulating macrophage-associated granulosa cell senescence during breast cancer chemotherapy

Erastin enhances metastatic potential of ferroptosis-resistant ovarian cancer cells by M2 polarization through STAT3/IL-8 axis

Erastin is a small molecule identified in chemical screen that is capable of inducing ferropotosis. There is collective evidence proving that erastin-induced ferroptosis exhibits anti-tumor potential within diverse caners, such as ovarian cancer (OC). However, most OC cells show relative resistance to ferroptosis induced by erastin. M2-polarized tumor-associated macrophages (TAMs) have an important effect on the OC tumor microenvironment (TME), which makes M2 polarization a noticeable part in the context of OC therapy. The immunomodulatory effects of erastin on ferroptosis-resistant OC cells remain poorly understood. Here, we found that low concentration of erastin greatly promoted ferroptosis-resistant OC cell invasion and migration via STAT3-mediated M2 polarization of macrophages. As revealed by in-vitro experimental results, erastin significantly increased metastases of ferroptosis-resistant OC, and the percentage of M2 macrophage infiltration was also raised after erastin treatment. Furthermore, erastin augmented IL-8 production of macrophages, and pharmacological blockage of IL-8 partially abrogated the stimulatory effect of erastin on ferroptosis-resistant OC cells. This study demonstrates a new mechanism undering the tumor-promoting activity of erastin and has implications for the STAT3/IL-8 axis as a potential target for ferroptosis-resistant OC cells to improve overall anti-tumor efficacy.

Radiomic model to predict the expression of PD-1 and overall survival of patients with ovarian cancer

Programmed cell death 1 (PD-1), encoded by programmed cell death protein 1 (PDCD1), is widely investigated in clinical trials. We aimed to develop a radiomic model to discriminate its expression levels patients with ovarian cancer (OC) and explore its prognostic value. Computed tomography (CT) images with the corresponding sequencing data and clinicopathological features were used. The volumes of interest were manually delineated. After extraction and normalization, the radiomic features were screened using repeat least absolute shrinkage and selection operator. A radiomic model for PD-1 prediction, radiomic score (rad_score), was developed using logistic regression and validated via internal 5-fold cross-validation. The Kaplan-Meier curves, COX proportional hazards model, and landmark analysis were used for survival analysis. The mRNA level of PDCD1 significantly affects the overall survival (OS) of OC patients. The rad_score for PDCD1 prediction was based on four features and was significantly correlated with other genes involved in T-cell exhaustion and immune checkpoint molecules. The areas under the receiver operating characteristic curves reached 0.810 and 0.772 in the training and validation datasets, respectively. The calibration curves and decision curve analysis proved the model's fitness and clinical benefits. Patients with higher rad_score had poorer OS (P < 0.001, 0.031, 0.014, 0.01, and < 0.001, after landmark of 12 months, before and after landmark of 36 months, and before and after landmark of 60 months, respectively). The radiomic signature from CT images can discriminate the PD-1 expression status and OC prognosis, which is correlated with T-cell exhaustion.

Advances in the application of immune checkpoint inhibitors in gynecological tumors

Immune checkpoints are regulatory molecules that suppress immune effector cells, and are essential for maintaining tolerance, preventing autoimmune reactions, and minimizing tissue damage by controlling the duration and intensity of the immune responses. However, immune checkpoints are frequently upregulated during cancer and dampen the anti-tumor immune responses. Immune checkpoint inhibitors (ICIs) have been effective against multiple tumors, and have improved patients' survival outcomes. Recent clinical trials have also reported promising therapeutic effects of ICIs in some gynecological cancers. To review the current research and future directions in the treatment of gynecological malignancies, including ovarian, cervical and endometrial cancers, using ICIs. Currently, cervical and ovarian cancers are the only gynecological tumors that are treated by immunotherapeutic approaches. In addition, ICIs, chimeric antigen receptor (CAR)- and T cell receptor (TCR)-engineered T cells targeting endometrial tumors, especially those originating in the vulva and fallopian tubes, are under development. Nevertheless, the molecular mechanism underlying the effects of ICIs, especially in combination with chemotherapy, radiation therapy, anti-angiogenesis drugs and poly ADP ribose polymerase inhibitors (PARPi), needs to be elucidated. Furthermore, novel predictive biomarkers have to be identified in order to increase the therapeutic efficacy of ICIs while reducing adverse reactions.

Prognostic significance of ferroptosis pathway gene signature and correlation with macrophage infiltration in cervical squamous cell carcinoma

Nuclear factor erythroid 2-related factor 2 (NFE2L2) plays a critical role in ferroptosis and biogenesis, however, its role in cervical squamous cell carcinoma (CESC) remains unknown. Therefore, in this study, we aimed to determine the role of NFE2L2 in CESC using multiomic analysis. All raw data were downloaded from The Cancer Genome Atlas (TCGA) and further validated in our dataset. NFE2L2 mRNA expression and methylation data on CESC were examined using the Tumor Immune Estimation Resource (TIMER) and University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database resources. NFE2L2 expression was examined in paraffin-embedded tissues from our cohort of 240 samples each of cancerous and non-cancerous tissues. Further, cervical cancer biopsies were genetically validated. TIMER and Tumor-Immune System Interactions Database (TISIDB) were used to analyze the correlation between NFE2L2 and cluster of differentiation 163 (CD163) with co-expressed genes in tumor-infiltrating immune cells. The mRNA and protein levels of NFE2L2 were lower in CESC tissues than they were in adjacent tissues. Importantly, a low NFE2L2 level correlated with poor prognosis in CESC patients. NFE2L2 was specifically expressed in tumor macrophages and correlated with the tumor immune landscape and poor prognosis in the cohort data. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis showed that co-expressed genes are mainly associated with multiple immune-related pathways. Furthermore, our data analysis revealed that NFE2L2 and macrophage CD163 expression levels were negatively correlated. Interestingly, we discovered multiple NFE2L2 binding sites in promoters of CD163. This study confirmed the novel pyroptosis landscape in CESC, provided a role for NFE2L2 in the tumor microenvironment, and identified prognostic biomarkers for CESC and related immune infiltration.

Methionine enkephalin inhibited cervical carcinoma via apoptosis promotion and reduction of myeloid derived suppressor cell infiltrated in tumor

Immunotherapy for cervical carcinoma is becoming increasingly important recently. In these studies methionine enkephalin (menk) is shown to inhibit cervical tumor cell proliferation in vitro in association with an increase in the expression of apoptosis markers and mediators, including an increase in fas, caspase 8, and caspase 3 expression and intrinsic expression of the signaling pathway mediator bax. In vivo, tumor growth was restrained in mice xenotransplant model with typical pathological features of apoptosis. Furthermore, myeloid derived suppressor cells (MDSCs) had a significant decrease in circulation and in tumor site. In brief, these findings showed menk could inhibit tumor growth in vitro and in vivo, providing direction of further research and clinical application prospect.

Cluster of differentiation frequency on antigen presenting-cells: The next step to cervical cancer prognosis?

Viruses may transform infected cells into benign or malignant tumors, promoting cell growth and survival via various intracellular pathways. Some oncogenic DNA viruses, such as human papillomaviruses, can lead to squamous intraepithelial lesions and cervical cancer. Furthermore, the early HPV virus'soncoproteins have been attributed to cancer initiation and development and tumor-enhancing action. In addition to viral oncoproteins, antigen-presenting cells (APC) and the number of clusters of differentiation (CD) markers expressed on their surface play an essential role in disease progression or tumorigenesis inhibition. This article discussed the function of CD markers in the interaction between APCs and cancer cells, immune cells' function in the infection process, and finally infected cells' malignancy. We investigated targeting these markers as a novel insight to create a new therapeutic or diagnosis strategy to prevent cervical cancer progression.

Effect of immunotherapy on the immune microenvironment in advanced recurrent cervical cancer

This study evaluated the basic immune status of cervical cancer and the influences of immunotherapy on the immune microenvironment, and analyzed the correlation between changes in the immune microenvironment and prognosis. We retrospectively analyzed the treatment status of 8 patients with advanced recurrent cervical cancer treated with PD-1 inhibitors and detected the tumor-infiltrating immune markers (CD3, CD4, CD8, CD20, CD56, CD68, PD-1, and PD-L1) by immunohistochemistry. All patients showed good tolerance during the treatment. Complete response (CR), partial response (PR) and stable disease (SD) was observed in 3, 2, and 3 patients, respectively. Immunohistochemical analysis showed immunotherapy resulted in increased infiltration of T lymphocytes, natural killer cells, and B cells, especially among those who responded well. The expression of B cells in 4 of the 5 patients with clinical benefit was relatively high, and the expression of PD-L1 in these 5 patients showed a combined positive score > 3. PD-L1 expression increased significantly after treatment with PD-1 inhibitors. Second-generation sequencing showed that the tumor mutation burden of two patients with adenocarcinoma was high, and after immunotherapy, one case recurred after cure and the other remained stable. PR was also observed in squamous cell carcinoma patients with dMMR (p.R2165H/c.6494G > A) and PIK3CA (p.E545K(E9)) mutations. The expression of B cells and PD-L1 has certain predictive effect for the efficacy of immunotherapy in cervical cancer under the condition of high or low T cell infiltration, and can inform treatment decision-making for patients with advanced cervical cancer.

Advancing cancer diagnosis and therapy: MXene-based biosensing and nanomedicine applications

Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway

From innate immunity to precision cancer therapy: the clinical advancement of NK cell therapy

B4M3 CAR-T cell enhance antitumor activity and non-tumor toxicity in ovarian cancer

Chimeric antigen receptor (CAR) T cells have demonstrated promising therapeutic outcomes in hematologic malignancies, but efficacy against most solid tumors, including ovarian cancer (OC). To address CAR-T challenges, we generated CAR-T cells (B4M3 CAR-T) targeting two tumor-associated antigens, B7H3 and MSLN, simultaneously. Immunohistochemistry and proteomics technologies, were employed to analyze the xenograft tumor tissues and key organ tissues at the end of the treatment in vivo assays. B4M3 CAR-T cells demonstrated rapid antitumor effects under in vivo stress conditions, protected against organ damage, and exhibited favorable safety and tolerability. Molecular and signaling studies indicated that B4M3 CAR-T promoted tumor cell death by activating the NF-κB and TNF signaling pathways. Furthermore, B4M3 CAR-T cells enhancing the innate immune response and altering the metabolic profile. Collectively, our study successfully developed B4M3 CAR-T cells, which exhibited significant antitumor effects in ovarian cancer and it provide a novel strategy for the immunotherapy of OC.

Bevacizumab increases cisplatin efficacy by inhibiting epithelial–mesenchymal transition via ALDH1 in cervical carcinoma

Cervical carcinoma has the highest incidence among gynaecological cancers in developing countries where the human papillomavirus (HPV) vaccine is not yet widely used. Cancer stem cells (CSCs) are the key factors affecting treatment efficacy and cancer prognosis. Aldehyde dehydrogenase 1 (ALDH1) is a marker of CSCs, and its expression is closely related to chemotherapy resistance in cervical carcinoma. Bevacizumab is the most widely used molecular targeted drug in the management of cervical carcinoma. We designed and performed a series of in vitro and in vivo experiments to investigate the inhibitory effects of these compounds on ALDH1 and the underlying mechanism involved. The results revealed that bevacizumab significantly inhibited epithelial-mesenchymal transition (EMT) in HeLa cervical cancer cells, as indicated by upregulation of E-cadherin and downregulation of N-cadherin and snail. Anoxic pressure was relieved, and tumour vascularization was inhibited in the tumour microenvironment. NOTCH1 plays a critical role in these processes. Through modulating these tumour biological characteristics via ALDH1, bevacizumab increases the sensitivity of cervical carcinoma to cisplatin, suggesting that bevacizumab in combination with standard chemotherapy may represent a new strategy for overcoming drug resistance. Abbreviation: HPV, human papillomavirus; CSCs, cancer stem cells; ALDH1, aldehyde dehydrogenase 1; EMT, epithelial-mesenchymal transition; OD, optical density; qRT-PCR, RNA analysis by quantitative real-time polymerase chain reaction; RIPA, radioimmunoprecipitation assay; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; PVDF, polyvinylidene difluoride; ECL, electrochemiluminescence; NC, negative control; HE, haematoxylin and eosin; IHC, immunohistochemistry; DAB, 3, 3'-diaminobenzidine; IF, immunofluorescence; DAPI, 4,6-diamidino-2-phenylindole; VEGFA, vascular endothelial growth factor A; ROS, oxygen species; DFS, disease-free survival; OS, overall survival; HIF, hypoxia-inducible factor; PDGFs, platelet-derived growth factors; FGFs, fibroblast growth factors; PlGF, placenta growth factor; RTKs, receptor tyrosine kinases.

Integrated analyses reveal CXCL11 as an inhibitor in ovarian cancer and its facilitation of an M1 macrophage switch via the JAK2/STAT1 pathway

M1-like tumor-associated macrophages (TAMs) have been put forth as a critical component in the advancement of cancer biology, including oncogenesis, development, invasion, metastasis, and the formation of tumor microenvironment (TME). Nevertheless, there has been a paucity of research examining the functions and associated molecular mechanisms of the M1-like TAMs in ovarian cancer (OC). The objective of this study is twofold: first, to gain a deeper understanding of the positive role of M1-like TAMs in OC; and second, to identify reliable biomarkers to stratify the risk of disease progression in OC patients via integrated analyses. Leveraging combined single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic data, we systematically identified M1 macrophage-associated molecules and established their prognostic significance in OC. CXCL11 was pinpointed as the central biomarker, with its protective role further validated through bioinformatics analyses and in vitro functional assays. Collectively, our findings advance the understanding of M1 macrophage-related molecular networks in OC and reveal CXCL11 as a dual-functional entity: a favorable prognostic biomarker and a positive regulatory molecule of M1 polarization via the JAK2-STAT1 pathway. These insights position CXCL11 as a promising therapeutic target and prognostic indicator for OC, offering a new perspective for the immunotherapy of OC.

Expression of membrane-bound Interleukin-15 sustains the growth and survival of CAR-NK cells

Tilianin regulates the proliferation, invasion and tumor immune microenvironment of thyroid cancer cells through the TLR4/NF-κB axis

m6A-Related SNPs in endometriosis and ovarian cancer: implications for chemoresistance and therapeutic targeting

Ovarian cancer (OC) is highly lethal, largely due to late diagnosis and chemoresistance. Endometriosis (EM) increases the risk of specific OC subtypes, but the molecular connection between the two diseases is still unclear. m6A RNA methylation may contribute to tumor progression and therapy resistance. This study investigated m6A-associated genetic variants and their regulatory roles in OC and EM, with a focus on mechanisms of cisplatin resistance. GWAS summary statistics were combined with m6A-associated variants from the RMVar database to identify disease-related m6A-SNPs. HaploReg was used for eQTL analysis. Single-cell RNA sequencing (scRNA-seq) data from chemotherapy-treated OC samples were analyzed to identify resistant tumor subpopulations and microenvironmental changes. TCGA data provided external validation, including drug sensitivity correlations. Functional assays were performed using LDHB overexpression and knockdown models. We identified 49 m6A-SNPs associated with OC and 110 associated with EM. Several showed eQTL effects on genes involved in immune regulation, oxidative stress, and cell adhesion. scRNA-seq revealed distinct drug-resistant epithelial subpopulations enriched for IFITM2, HLA-DQB1, and metabolic regulators, along with increased infiltration of macrophages, fibroblasts, and B-cell lineages. TCGA pharmacogenomic analysis demonstrated a strong negative correlation between LDHB expression and cisplatin sensitivity. Functional experiments showed that LDHB overexpression promoted cisplatin resistance, enhanced migration, and reduced apoptosis, whereas LDHB knockdown had opposite effects. This study identifies m6A-related SNPs as important regulatory factors shared between OC and EM. By integrating genetic, transcriptomic, and functional data, we highlight immune and metabolic pathways-especially those involving LDHB, IFITM2, and HLA-DQB1-as key contributors to cisplatin resistance. These findings provide potential therapeutic targets and a framework for understanding m6A-associated mechanisms in ovarian cancer progression. Further in vivo studies are needed to validate the direct effects of specific m6A-SNPs.

UBC6 mediated the inhibitory effect of quercetin on ovarian cancer through the PRKN-AURKA-AMPK axis

Ovarian cancer (OC) is the most lethal gynecological malignancy with high recurrence rate and short survival. As a kind of phytochemical, quercetin has been demonstrated as a broad spectrum of antitumor activities. Ubiquitin-conjugating enzyme E2 J1 (UBC6) was screened as a candidate target of quercetin by Label-free proteomic analysis. However, the function and mechanisms of UBC6 in OC development remain largely unknown. In this study, lentiviruses targeting UBC6 were constructed to infect Caov-3 and SKOV-3 cells and an OC mouse model was constructed by injecting 5 × 10

The neutrophil–NET Axis in ovarian cancer: Drivers of tumor microenvironment remodeling and therapeutic resistance

Ovarian cancer remains the most lethal gynecologic malignancy, characterized by profound molecular heterogeneity, immune evasion, and resistance to therapy. Despite surgical and chemotherapeutic advances, recurrence and omental metastasis persist, underscoring an incomplete understanding of the inflammatory circuits sustaining disease progression. Recent insights reveal that neutrophils are not passive responders but active architects of the ovarian tumor microenvironment (TME). Tumor-derived cytokines (IL-8, G-CSF, CXCL1/2) and metabolic cues such as hypoxia and lactate drive their polarization toward a pro-tumor phenotype and trigger NETosis-the release of chromatin webs decorated with histones and proteases. These neutrophil extracellular traps (NETs) remodel the TME by enhancing vascular permeability, supporting angiogenesis, and providing adhesive scaffolds for peritoneal implantation. Beyond their structural role, NETs promote immune escape by degrading chemokines essential for cytotoxic T-cell recruitment, engaging pattern-recognition receptors, and activating NF-κB- and STAT3-dependent pro-survival signaling in tumor and stromal cells. This dual function-linking innate immune dysregulation with metastatic competence-positions NETosis as a pivotal determinant of ovarian cancer progression. This review integrates emerging data on neutrophil-tumor crosstalk, delineating how ovarian cancer cells exploit NET-related pathways, including PAD4 activation, ROS amplification, and cytokine feedback loops, to construct a pro-metastatic niche within the omentum. Finally, we highlight the therapeutic promise of targeting NETosis through PAD4 inhibitors, DNase-based strategies, and immunomodulatory interventions aimed at reprogramming the tumor-neutrophil axis. By decoding this neutrophil-NET-tumor network, we propose a paradigm in which dismantling NETosis could limit metastasis, restore immune surveillance, and improve therapeutic sensitivity in ovarian cancer.

The interaction between IL-33 and TRIM28 in the regulation of macrophage polarization in an ST2-independent manner

The tumor microenvironment provides optimal condition for the growth of ovarian cancer. Macrophages display a highly functional plasticity to respond various signals. Switching macrophages' phenotype is a potential therapeutic strategy for the treatment of cancer. We used RNA-sequencing(RNA-Seq) and Chromatin immunoprecipitation-sequencing(ChIP-Seq) analyses in bone-marrow-derived macrophages (BMDMs) from wild-type (WT) and its receptor interleukin-1 receptor like-1 (IL1RL1 or ST2) knockout(ST2

Pan-cancer analysis of DCBLD1 and its association with the diagnosis, immunotherapy, and prognosis of cervical cancer

Cervical cancer (CESC) is a leading cause of death attributed to cancer worldwide. Advanced-stage cervical cancer presents unique challenges, such as few treatment modalities. Though DCBLD1 has been earlier connected to a variety of cancers, there has been no extensive investigation on DCBLD1 regarding cervical cancer. This study seeks to assess the expression and prognostic significance of DCBLD1 in multiple cancer types, heavily relying on cervical cancer, as well as its implications on immune modulation. The pan-cancer expression of box-like genes in DCBLD1 was investigated in 33 cancer types using The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Survival analyses involving Overall Survival (OS) and Progression-Free Survival (PFS) were conducted to evaluate the relationship between DCBLD1 expression and the prognosis of these neoplasms. Furthermore, immune infiltration gene co-expression and tumor microenvironment (TME) analyses were performed. In vitro assays in cervical cancer cell lines were done to analyze the functional impact of silencing DCBLD1 on cell proliferation, migration, and invasion. DCBLD1 was significantly overexpressed in 16 cancer types, including cervical cancer, and was associated with poor prognosis for several of these cancer types. In CESC, the expression of DCBLD1 was significantly associated with shorter OS and PFS. While immune infiltration analysis showed a significant association for DCBLD1 with several immune cells, including CD4+ memory T cells and macrophages, the functional assays demonstrated that silencing DCBLD1 in cervical cancer cells inhibited their cell proliferation, migration, and invasion, implicating it in tumor progression. DCBLD1 could serve as an amendable biomarker of poor prognosis in cervical cancer and other cancers whose high expression level correlates with immune infiltration, which may suggest its role in modulating the tumor microenvironment. This shows that targeting DCBLD1 could prove effective as a potential therapeutic modality in conjunction with other immune-based therapies for cervical cancer.

Single‑cell RNA sequencing reveals heterogeneity in ovarian cancer and constructs a prognostic signature for prognostic prediction and immunotherapy

Ovarian cancer (OC) is one of the cancers with a high incidence at present, which poses a severe threat to women's health. This study focused on identifying the heterogeneity among malignant epithelial cell OC and constructing an effective prognostic signature to predict prognosis and immunotherapy according to a multidisciplinary study. The InterCNV algorithm was used to identify the heterogeneity of OC based on the scRNA-seq and bulk RNA-seq data. Six algorithms selected EMTscore. An effective prognostic signature was conducted using the COX and Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithms. The texting datasets were used to assess the accuracy of the prognostic signature. We evaluated different immune characteristics and immunotherapy response differences among other risk groups. A prognostic signature including 14 genes was established. The patients in the high-risk group have poor survival outcomes. We also found that the patients in the low-risk group have higher immune cell infiltration, enrichment of immune checkpoints, and immunotherapy response, suggesting that the patients in the low-risk group may be more sensitive to immunotherapy. Finally, the laboratory test results showed that KREMEN2 was identified as a novel biomarker and therapeutic target for OC patients. Our study established a GRG signature consisting of 16 genes based on the scRNA-seq and bulk RNA-seq data, which provides a new perspective on the prediction of prognosis and treatment strategy for OC.

Lactate inhibits interferon-α response in ovarian cancer by inducing STAT1 ubiquitin degradation

The emergence of lactate, produced by lactate dehydrogenase A (LDHA), as an important regulator of the immune response in tumor development has garnered attention in recent research. But, many questions still need to be clarified regarding the relationship between lactate and anti-tumor immunity. Here, we reported that both exogenous and endogenous lactate reduced the protein level and activation of the signal transducer and activator of transcription 1(STAT1) in ovarian cancer cells. As a consequence, the expression of IFNα-STAT1 regulated genes was weakened. This, in turn, weakened the antitumor effect of IFNα by impeding NKT and CD8

PD-1 and TIGIT coexpressing CD8 + CD103 + tissue-resident memory cells in endometrial cancer as potential targets for immunotherapy

Immunotherapy has shown promise in treating various cancers; however, its efficacy in endometrial cancer (EC) remains suboptimal owing to the complex dynamics of the tumour immune microenvironment. This study focuses on exploring the potential of targeting the programmed cell death protein 1 gene (PD-1) and the T cell Immunoreceptor with Ig and ITIM domains gene (TIGIT) coexpressing tissue-resident memory cells in EC. A comprehensive approach, utilizing RNA sequencing, single-cell RNA sequencing, mass cytometry, and flow cytometry, was employed to analyse the expression patterns of PD-1 and TIGIT in the EC tumor environment and to characterize the phenotypic properties of tumor-infiltrating lymphocytes (TILs), particularly tissue-resident memory (T Our analysis identified a significant co-expression of PD-1 and TIGIT in T T

The role of BATF2 deficiency in immune microenvironment rearrangement in cervical cancer – New biomarker benefiting from combination of radiotherapy and immunotherapy

Despite the significant progress in immunotherapy for certain cancers, including cervical cancer, most patients remain unresponsive or derive limited benefits from combined radiotherapy and chemotherapy. The factors underlying treatment resistance are unknown and there are few reliable predictive biomarkers. BATF2 is a member of the basic leucine zipper transcription factor family and is involved in immune response and immune cell development. However, the role of BATF2 in the immune microenvironment of patients with cervical cancer after radiotherapy remains unclear. In this study, immunohistochemistry and multicolour immunofluorescence analyses of patient tumor samples were used to assess BATF2 expression. We found that cervical cancer patients with high BATF2 expression had higher infiltration levels of CD4

Methionine enkephalin inhibited cervical cancer migration as well as invasion and activated CD11b+ NCR1+ NKs of tumor microenvironment

This study was to study the role of methionine enkephalin (menk) in cell invasion and migration as well as NK cells activation of tumor microenvironment in cervical cancer. The results showed that menk inhibited cervical cancer migration and invasion. In addition, we found menk affected epithelial to mesenchymal transition (EMT) related indicators, with increasing E-cadherin level, decreasing N-cadherin and vimentin level. Through in vivo mouse model, we found that menk IFNγ and NKP46 expression was upregulated in tumor tissues by menk compared with controls, while LAG3 expression was inhibited by menk, besides, there was an upregulation of CD11b

Immunotherapy checkpoints in ovarian cancer vasculogenic mimicry: Tumor immune microenvironments, and drugs

Vasculogenic mimicry (VM), a vessel-like structure independent of endothelial cells, commonly exists in solid tumors which requires blood vessels to grow. As a special source of blood supply for tumor progression to a more aggressive state, VM has been observed in a variety of human malignant tumors and is tightly associated with tumor proliferation, invasion, metastasis, and poor patient prognosis. So far, various factors, including immune cells and cytokines, were reported to regulate ovarian cancer progression by influencing VM formation. Herein, we review the mechanisms that regulate VM formation in ovarian cancer and the effect of cells, cytokines, and signaling molecules in the tumor microenvironment on VM formation, Furthermore, we summarize the current clinical application of drugs targeting VM formation.

Interaction between TMEFF1 and AHNAK proteins in ovarian cancer cells: Implications for clinical prognosis

TMEFF1 is a newly discovered protein involved in the physiological functions of the central nervous system, embryonic development, and other biological processes. Our previous study revealed that TMEFF1 acts as a tumor-promoting gene in ovarian cancer. AHNAK, as a giant scaffolding protein, plays a role in the formation of the blood-brain barrier, cell architecture and the regulation of cardiac calcium channels. However, its role in ovarian cancer remains poorly researched. In this study, we detected the expression of AHNAK and TMEFF1 in 148 different ovarian cancer tissues, determined their relationship with pathological parameters and prognosis, clarified the interaction between the two proteins, and explored the related cancer-promoting mechanisms through immunohistochemistry, immunoprecipitation, immunofluorescence double staining, western blotting, and bioinformatics. The high expression of ANHAK and TMEFF1 in ovarian cancer indicated a higher degree of tumor malignancy and a worse prognosis. Furthermore, the expression of TMEFF1 and AHNAK was significantly positively correlated. The results also showed that AHNAK and TMEFF1 co-localized and interacted with each other in ovarian cancer tissues and cells. And knockdown of AHNAK promoted proliferation, migration and invasion of ovarian cancer cells in vitro. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that AHNAK and related genes were enriched during mitosis regulation, cytoskeleton formation, gene epigenetics, etc., whereas TMEFF1 and related genes are enriched during immune regulation and other processes. We also clarified the network of kinases, microRNA, and transcription factor targets, and the impact of genetic mutations on prognosis. Notably, AHNAK was regulated by the expression of TMEFF1 and can activate the MAPK pathways. Overall, high expression of AHNAK and TMEFF1 in ovarian cancer cells indicated a higher degree of tumor malignancy and a worse prognosis. Therefore, the interaction between AHNAK and TMEFF1 may become a potential anti-tumor target for ovarian cancer treatment.

PD-L1: Can it be a biomarker for the prognosis or a promising therapeutic target in cervical cancer?

Cervical cancer is one of the most common in the female genital tract and remains a leading cause that threatens the health and lives of women worldwide, although preventive vaccines and early diagnosis have reduced mortality. While treatment by operation and chemoradiotherapy for early-stage patients achieve good outcomes, the great majority of cervical cancers caused by the human papilloma virus (HPV) make immunotherapy realizable for patients with advanced and recurrent cervical cancer. To date, some clinical trials of checkpoint immunotherapy in cervical cancer have indicated significant benefits of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors, providing strong evidence for PD-1/PD-L1 as a therapeutic target. In this review article, we discuss the role of PD-L1 and the application of PD-L1 inhibitors in cervical cancer, with the aim of providing direction for future research.

OTUD4-mediated inhibition of YAP1 signaling pathway in ovarian cancer: Implications for macrophage polarization and recruitment

Ovarian cancer is a malignancy gynecologic oncology with high incidence and high mortality rate. M2-like tumor-associated macrophages promote cancer cell migration and metastasis. Ovarian tumor family deubiquitinase 4 (OTUD4) belongs to deubiquitinating enzyme family. The roles of OTUD4 in tumor microenvironments in ovarian cancer remains unknow. In this work, OTUD4 was overexpressed or knocked down in high-grade serous ovarian cancer cells OVCAR8 and CAOV3. Ovarian cells were co-cultured with THP-1 macrophages to simulate the tumor microenvironment. We found that OTUD4-expressed ovarian cells inhibited macrophage chemotaxis and M2 polarization. Besides, in ovarian tumor-bearing mouse model, OTUD4 suppressed tumor metastasis and remodeling tumor-associated macrophages phenotype (pro-tumor M2 to anti-tumor M1). In mechanism, OTUD4 protein bound to YAP1 protein, and downregulation of OTUD4 enhanced K63 ubiquitination and nuclear translocation of YAP1, thus increasing CCL2 transcription and subsequent macrophage recruitment. OTUD4 might inhibit CCL2 expression to regulate tumor-associated macrophages in ovarian tumor microenvironment. Those findings present a potential therapeutic strategy for ovarian cancer.

TGF β1 promotes the polarization of M2-type macrophages and activates PI3K/mTOR signaling pathway by inhibiting ISG20 to sensitize ovarian cancer to cisplatin

The involvement of Interferon-stimulated exonuclease gene 20 (ISG20) has been reported in renal clear cell carcinoma, hepatocellular carcinoma, and cervical cancer. However, its role in ovarian cancer chemotherapy remains unclear. In this study, we conducted a comparative analysis of TGF-β1 and ISG20 in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells and tissues using qRT-PCR and a tissue immunofluorescence analysis. We also investigated the impact of ISG20-targeted drugs (IFN-γ) and TGF-β1 inhibitors on cisplatin response both in vivo and in vitro. Additionally, we assessed the effects of TGF-β1 or ISG20 on the polarization of tumor-associated macrophages through flow cytometry and ELISA analysis. Our findings revealed that ISG20 expression was lower in cisplatin-resistant tissues compared to cisplatin-sensitive tissues; however, overexpression of ISG20 sensitized ovarian cancer to cisplatin treatment. Furthermore, activation of ISG20 expression with IFN-γ or TGF-β1 inhibitors enhanced the sensitivity of ovarian cancer cells to cisplatin therapy. Notably, our results demonstrated that TGF-β1 promoted M2-type macrophage polarization as well as PI3K/mTOR pathway activation by suppressing ISG20 expression both in vivo and in vitro. In conclusion, our study highlights the critical role played by ISG20 within the network underlying cisplatin resistance in ovarian cancer. Targeting ISG20 using IFN-γ or TGF-β1 inhibitors may represent a promising therapeutic strategy for treating ovarian cancer.

Lactate drives the ESM1–SCD1 axis to inhibit the antitumor CD8+ T-cell response by activating the Wnt/β-catenin pathway in ovarian cancer cells and inducing cisplatin resistance

Ovarian cancer (OC) is a gynecological malignancy that results in a global threat to women's lives. Lactic acid, a key metabolite produced from the glycolytic metabolism of glucose molecules, is correlated with tumor immune infiltration and platinum resistance. In our previous study, we found that endothelial cell-specific molecule 1 (ESM1) plays a key role in OC progression. This study revealed that lactate could upregulate ESM1, which enhances SCD1 to attenuate the antitumor CD8

Prospects and challenges of CAR-T in the treatment of ovarian cancer

Ovarian cancer ranks as the seventh most prevalent cancer among women and is considered the most lethal gynecological malignancy on a global scale. The absence of reliable screening techniques, coupled with the insidious onset of nonspecific symptoms, often results in a delayed diagnosis, typically at an advanced stage characterized by peritoneal involvement. Management of advanced tumors typically involves a combination of chemotherapy and cytoreductive surgery. However, the therapeutic arsenal for ovarian cancer patients remains limited, highlighting the unmet need for precise, targeted, and sustained-release pharmacological agents. Genetically engineered T cells expressing chimeric antigen receptors (CARs) represent a promising novel therapeutic modality that selectively targets specific antigens, demonstrating robust and enduring antitumor responses in numerous patients. CAR T cell therapy has exhibited notable efficacy in hematological malignancies and is currently under investigation for its potential in treating various solid tumors, including ovarian cancer. Currently, numerous researchers are engaged in the development of novel CAR-T cells designed to target ovarian cancer, with subsequent evaluation of these candidate cells in preclinical studies. Given the ability of chimeric antigen receptor (CAR) expressing T cells to elicit potent and long-lasting anti-tumor effects, this therapeutic approach holds significant promise for the treatment of ovarian cancer. This review article examines the utilization of CAR-T cells in the context of ovarian cancer therapy.

Tamoxifen induced cardiac damage via the IL-6/p-STAT3/PGC-1α pathway

GSG2 promotes progression of human endometrial cancer by regulating PD-1/PD-L1 expression via PI3K-AKT pathway

Cell cycle dysregulation leading to uncontrolled growth is a primary characteristic of malignancy. GSG2, a mitosis-related kinase, affects the normal cell cycle by interfering with the normal dissociation of centromere cohesion, and its overexpression has been shown to play an important role in cancer cells. Here, we investigated the function of GSG2 as a tumor promoter in endometrial carcinoma and its relationship with the immunological microenvironment. We used immunohistochemistry to identify a correlation between the development and prognosis of GSG2 and endometrial cancer. Cell and animal experiments confirmed that GSG2 has a protumorigenic phenotype in endometrial cancer cell lines. Furthermore, using GeneChip analysis and a tumor-immune coculture model, we observed a link between GSG2 expression and the composition of the immune microenvironment. Therefore, we concluded that the activation of the PI3K/AKT pathway by GSG2 may impact DNA repair, disrupt the cell cycle, and regulate the immune response, all of which could increase the ability of EC cells to proliferate malignantly. Consequently, it is anticipated that GSG2 will be a viable therapeutic target in endometrial carcinoma.

Maackiain induces apoptosis and autophagy via ROS-mediated endoplasmic reticulum stress in endometrial cancer

Endometrial cancer (EC) is a common gynecological cancer, characterized by increasing incidence and mortality rates. Maackiain (MA), a natural flavonoid compound, has multiple biological activities, but little is known about how it affects EC cells. In the present study, CCK-8, EdU, colony formation, and flow cytometry assays were used to evaluate the effects of MA on EC cell proliferation, apoptosis, and reactive oxygen species (ROS) levels. The effect of MA on autophagy in EC cells were examined through the observation of cell morphology and ultrastructure, and cells were transfected with AdPlus-mCherry-GFP-LC3B for further analysis. Transcriptomic and western blot analyses revealed the underlying mechanism. To evaluate the anti-EC effect of MA in vivo, a xenograft model was established. The results demonstrated that MA inhibited KLE and Ishikawa cell growth in a dose-dependent manner. Furthermore, MA significantly suppressed EC xenograft tumor growth in vivo while exhibiting low toxicity. In addition, EC cells treated with MA exhibited pro-apoptotic and pro-autophagic responses, with the latter exhibiting cytoprotective properties. MA also induced the accumulation of ROS, which promoted endoplasmic reticulum (ER) stress. Notably, the use of the N-acetyl-L-cysteine (NAC) ROS scavenger and the 4-phenylbutyric acid (4-PBA) ER stress inhibitor effectively mitigated the autophagy and apoptosis induced by MA. These results collectively implied that MA triggers autophagy and apoptosis in EC cells through ROS-mediated ER stress, highlighting its potential as a therapeutic agent against EC.

The combined immunization of cervical cancer therapeutic vaccine based on Listeria balanced lethal system has a significant therapeutic effect on tumor model mice

Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer death in women. Effective treatment of cervical cancer is urgently needed. Tumor therapeutic vaccine is a research hotspot in tumor immunotherapy, and the tumor therapeutic vaccine based on attenuated live bacteria carrier has clinical application prospect because of its clear action site and high safety. The bacterial balanced lethal system uses nutritional screening instead of antibiotic screening to avoid the risk of the spread of antibiotic resistance. So it is generally recognized as a green carrier. In our early research, we have constructed two cervical cancer therapeutic vaccine candidates (LM-HPVCW-1 and LI-HPVCW-1) based on Listeria balanced lethal system via transforming the nutrient-deficient strains with nutrition gene complementary plasmid. The complementary plasmid contained the nutrition complementary gene, LM dal gene, and its Amp gene was replaced with asd gene to delete the antibiotic resistance. Besides, it carried the shuffled HPV-16 E6E7 fusion protein gene. In vitro experiments showed that the plasmid carried by the candidate strain could be stably passaged and the target protein could be successfully expressed. In this study, we proved that the two candidate strains were safe in vivo and induced cellular immune response. At the same time, by establishing a tumor-bearing mouse model, it was proved that the two vaccine strains combined immunization could effectively inhibit mouse tumors. The mechanism of tumor suppression may be related to breaking the immunosuppression of tumor microenvironment and inducing CD8

The Prominence of the Broad-Spectrum Protease inhibitor gene A2ML1 as a potential biomarker in cervical cancer diagnostics using Immunotherapeutic and Multi-Omics approaches

One of the venereal tumors that threaten human life is cervical cancer. A2ML1 is detected in advanced-stage cancer patients and is found to be strongly associated with cervical cancer. A2ML1 was shown to be substantially expressed in cervical cancer in this study, which used data from the TCGA database. Those with high A2ML1 expression had a lower chance of survival than patients with low A2ML1 expression. Both univariate and multivariate Cox regression analyses were utilized to investigate the relationship between clinical variables and overall survival rates. An investigation into the link between A2ML1 and immune infiltration was subsequently conducted. Utilizing the immune cell database, research was conducted to investigate the dispersion of 24 immune cells and their correlation to A2ML1 expression. In addition to this, the favorable correlation between immune cells and A2ML1 was validated using all three immune cell methodologies. The Genomics of Drug Sensitivity in Cancer database was used to confirm the idea that there is a link between A2ML1 expression and the efficacy of chemotherapy or immunotherapy. The findings demonstrated that A2ML1 is a potential biomarker for cervical cancer diagnostics. This biomarker may be used to chaperone immunotherapy, as well as to explain the elucidates of cervical cancer caused by the immunological microenvironment.

Effects of curcumin nanoparticles on the proliferation and migration of human ovarian cancer cells assessed through the NF-κB/PRL-3 signaling pathway

Curcumin (CUR) exhibits potential inhibitory effects on tumor growth; however, its hydrophobicity and instability limit its clinical applications. In the present study, we developed CUR nanoparticles (CUR-NPs) and evaluated their biochemical characteristics. Cell uptake and proliferation were assessed using scratch and Transwell assays, respectively. Western blotting was performed to investigate the expression levels of proteins related to the NF-κB/PRL-3 signaling pathway, inflammatory response, cell proliferation, and cell migration in SKOV3 cells. Our findings showed that the blank vector was not cytotoxic to cells, allowing us to disregard any effects caused by the vector itself. CUR-NPs exhibited concentration- and time-dependent inhibitory effects on cell proliferation, surpassing those of CUR alone. Increasing the concentration of CUR-NPs resulted in a reduced cell scratch-healing ability and lower chamber migration capacity. Compared to the control group, expression levels of proteins associated with NF-κB/PRL-3 signaling pathway, inflammatory response (TNF-α and IL-6), cell proliferation (cyclin E1 and cyclin A1), as well as cell migration (N-cadherin and vimentin) were significantly elevated in the lipopolysaccharide (LPS) stimulation and NF-κB p65 overexpression groups. Conversely, E-cadherin expression was significantly decreased under these conditions. However, treatment with high concentrations of CUR-NPs effectively reversed these changes. These results highlight the significant ability of CUR-NPs to inhibit human ovarian cancer cell proliferation and migration, while suppressing inflammatory responses through the regulation of the NF-κB/PRL-3 signaling pathway.

CYP24A1 affected macrophage polarization through degradation of vitamin D as a candidate biomarker for ovarian cancer prognosis

Ovarian cancer (OC) is a fatal gynecological malignancy with a poor prognosis in which mitochondria-related genes are involved deeply. In this study, we aim to screen mitochondria-related genes that play a role in OC prognosis and investigate its effects. Through single-cell sequencing technology and bioinformatics analysis, including TCGA ovarian cancer data analysis, gene expression signature analysis (GES), immune infiltration analysis, Gene Ontology (GO) enrichment analysis, Gene Set Enrichment Analysis (GSEA), and Principal Component Analysis (PCA), our findings revealed that CYP24A1 regulated macrophage polarization through vitamin D (VD) degradation and served as a target gene for the second malignant subtype of OC through bioinformatics analyses. For further validation, the expression and function of CYP24A1 in OC cells was investigated. And the expression of CYP24A1 was much higher in carcinoma than in paracancerous tissue, whereas the VD content decreased in the OC cell lines with CYP24A1 overexpression. Moreover, macrophages were polarized towards M1 after the intervention of VD-treated OC cell lines and inhibited the malignant phenotypes of OC. However, the effect could be reversed by overexpressing CYP24A1, resulting in the polarization of M2 macrophages, thereby promoting tumor progression, as verified by constructing xenograft models in vitro. In conclusion, our findings suggested that CYP24A1 induced M2 macrophage polarization through interaction with VD, thus promoting the malignant progression of OC.

Multi-omics identifies OSM-OSMR as a key receptor-ligand in the tumor environment of endometrial adenocarcinoma

Endometrial adenocarcinoma carries a bleak prognosis, and the molecular markers that evaluate the progression of endometrial adenocarcinoma to advanced stages remain uncertain. Cell-cell communication plays a crucial role in the tumor microenvironment. We aimed to explore the ligand-receptor relationship between tumor cells and other cells and construct a prognostic model. To make further investigation, we downloaded and analyzed datasets of single-cell RNA-seq, spatial transcriptome sequencing for EC from GEO, bulk RNA sequencing and clinical data of TCGA-EC project from TCGA. Compared to the adjacent normal tissue, there is a significantly elevated Oncostatin M (OSM) signaling in the cell communication intensity and quantity of endometrial cancer tissues through analyzing the scRNA-seq dataset. Endometrial adenocarcinoma can be divided into four subtypes based on the OSM gene set. By comparing multiple machine learning methods, we have identified the random survival forest method as having the highest C-index. Based on this method, we constructed a seven-gene signature model to predict the survival prognosis of endometrial adenocarcinoma. The exogenous cytokine OSM induced Ishikawa cell proliferation and abnormal lipids metabolism, while the transcriptome sequencing results reveal that the pathways enriched with differentially expressed genes include AKT signaling pathways. The OSMR-knockout inhibited the tumorigenicity of Ishikawa Cells in the subcutaneous xenotransplanted tumor model of endometrial cancer. Our analysis revealed that OSM promotes the proliferation of Ishikawa cells via the AKT signaling pathway, abnormal lipids metabolism highlighting its significance in the regulation of TME. The prognostic model can provide valuable insights into guiding treatment strategies and suggesting further clinical management of endometrial adenocarcinoma patients.

Anti-tumour effect of in situ vaccines combined with VEGFR inhibitors in the treatment of metastatic cervical cancer

Cervical cancer is the fourth most common malignant tumor in the world, for advanced cervical cancer, more than 30% of patients continue to have tumor and relapse or metastasis after the traditional treatment (concurrent chemoradiotherapy), and the response rate of immune checkpoint inhibitor (PD-1) is less 15%, so additional approaches are required. In situ vaccine is a very promising immunotherapy strategy. In the preclinical study, the combination of CPG and anti-Ox40 antibody can completely resolve injection site tumours and distant tumours and leads to the recovery of most mice with lymphoma. However, our early exploration process found that the effect of CpG + OX40 in the treatment of advanced cervical cancer is not ideal. Hence, we explored the anti-tumor effect of CpG + OX40 combined with anti-angiogenic therapy for the first time. The results showed that the combination significantly inhibited the proliferation of primary and secondary tumor volume and prolonged the survival time of mice, compared with the control group, CD3+, CD4 + and CD8 + T cells in the combined group showed an increasing trend. In addition, in terms of metabolism, the anti-vascular effect of anlotinib can significantly reduce the blood supply and metabolic level of tumor, the expression of Ki67 and CD31 in the control group was significantly higher than that in each administration group. In conclusion, our preclinical research results showed that the combination of in situ vaccine and anti-angiogenic therapy has a good anti-tumor effect, and may potentially offer an effective treatment option for patients with advanced cervical cancer.

SPP1 enhances radiotherapy resistance through CCL2-mediated M2-like polarization of macrophages in cervical Cancer

Late-stage cervical cancer often exhibits poor responses to radiotherapy and immunotherapy, but the key regulatory factors and mechanisms underlying these issues remain inadequately understood. In the current study, we reveal that the expression level of SPP1 correlates positively with pathological grading, and patients with higher SPP1 expression show poorer response to radiotherapy and worse clinical outcomes. Analysis of clinical dataset reveals that SPP1 expression is associated with M2-like polarization of tumor-associated macrophages, a process known to closely relate to resistance against tumor immunotherapy. In co-culture systems of cervical cancer cells and macrophages, either knockdown or overexpression of SPP1 can correspondingly inhibit or promote M2-like polarization. RNA-seq data analysis of SPP1 knockdown cervical cancer cell lines indicates that SPP1 enhances the expression of CCL2, a crucial factor that drives M2-like polarization of macrophage. In vivo experiments demonstrate that inhibiting SPP1 expression in cervical cancer effectively suppresses p-STAT3 expression level and M2-like polarization of macrophages, thereby alleviates cervical tumor progression. Our study elucidates the mechanism by which SPP1 contributes to progression of cervical cancer and provides a theoretical basis for the development of targeted therapeutic strategies aimed at advancing precision medicine.

Real-world outcomes of first-line maintenance therapy for recurrent or metastatic cervical cancer: A multi-center retrospective study

Maintenance therapy (MT) for recurrent or metastatic cervical cancer remains non-standardized. This study assessed MT effectiveness using a comprehensive approach and identifies prognosis factors inpatients with recurrent or metastatic cervical cancer. From January 2019 and December 2021, over 6000 patients from six Chinese institutions were retrospectively examined. Patients had recurrent/metastatic cervical cancer and underwent first-line chemotherapy with or without MT. We calculated overall and progression-free survival using Kaplan-Meier analysis, comparing via log-rank test, and conducted Cox regression for prognostic factors. Overall, 274 patients were stratified into an MT group (n = 77) and a non-MT group (n = 197). The 3-year OS rates were 52.5 % and 28.0 % for the MT and non-MT groups, respectively. The MT group had significantly enhanced median OS (37 vs. 21 months; HR, 0.43; 95 % CI, 0.30-0.61; P  8 MT cycles. Multivariate analyses revealed that oligometastasis, MT, exclusive prior surgery (as opposed to combined surgery and radiotherapy), and extended interval before recurrence were independent OS predictors (P = 0.045, P < 0.001, P = 0.010, and P = 0.005, respectively); oligometastasis, concurrent radiotherapy, MT, and extended interval before recurrence were independent PFS predictors (P = 0.004, P = 0.007, P = 0.009, and P = 0.003). The MT integration markedly extended PFS and OS in patients diagnosed with recurrent or metastatic cervical cancer.

Association between tumor mutation burden and immune infiltration in ovarian cancer

It remains unclear whether the tumor mutation burden (TMB) or a TMB-related signature could be prognostic indicators in ovarian cancer (OC), as potential correlations with immune infiltrates and immunotherapy responsiveness remains poorly understood. Data of 941 OC patients were collected from three datasets, including 587, 260, and 94 patients from The Cancer Genome Atlas (TCGA), GSE32062, and the International Cancer Genome Consortium (ICGC), respectively. TMB was calculated and correlations with clinical outcomes, immune infiltrates, and immunotherapy responsiveness were investigated in the TCGA OC cohort. Weighted gene co-expression network analysis was performed to identify TMB-related genes. A TMB-related signature was constructed and validated. Higher TMB was associated with better survival in the TCGA and ICGC OC cohorts. The high-TMB group had higher CD8+ T-cell infiltration than the low-TMB group. No significant correlation was found between TMB and immunotherapy response. Furthermore, we selected 8 prognostic and TMB-related genes to construct a TMB-related signature that could distinguish between the high- and low-risk patients; its predictive power was validated in the GSE32062 and ICGC datasets. SubMap analysis suggested that patients in the low-risk group might have a better response to anti-PD1 therapy. We examined the prognostic value of TMB and its potential association with immune cell infiltration and immunotherapy responsiveness in OC. A TMB-related prognostic signature consisting of 8 genes was developed and verified, which might be a promising prognostic signature for the prognosis of OC patients.

Targeting SPP1+ macrophages via the SPP1-CD44 axis reveals a key mechanism of immune suppression and tumor progression in ovarian cancer

Tumor-associated macrophages (TAMs) play a pivotal role in immune suppression, tumor progression, and metastasis within the tumor microenvironment (TME) of ovarian cancer. While TAMs are known to promote T-cell dysfunction, the precise molecular mechanisms governing this process remain poorly understood. Here, we performed an integrated analysis of six high-grade serous ovarian cancer (HGSOC) single-cell sequencing datasets to investigate the molecular and functional diversity of TAMs in HGSOC. We identified an SPP1

IL17A/F secreted by ASCT2-overexpression ovarian cancer cells contributes to immune escape through the suppression of natural killer (NK) cells cytotoxicity by the activation of c-JUN/ PTGS2 pathway

Ovarian cancer (OC) is a deadly gynecologic cancer associated with metastasis, recurrence, and treatment resistance. The expression of the alanine-serine-cysteine transporter 2 (ASCT2) has been linked to poor prognosis and immune cell infiltration in OC tumors, but the underlying mechanisms are unclear. Lentiviral constructs were used to manipulate ASCT2 expression in OC cells (SKOV-3). The effects of ASCT2 on SKOV-3 behaviors including proliferation, invasion, migration, apoptosis, and cell cycle were assessed using various assays. The correlation between ASCT2 expression and immune infiltration in OC was analyzed using the Cancer Genome Atlas (TCGA) database. Co-culture experiments were conducted to evaluate the impact of ASCT2 overexpression in SKOV-3 on NK cells, followed by transcriptomics and cytokine analysis. ASCT2 expression and cytokine levels were characterized using qPCR and western blotting. ASCT2 overexpression significantly promoted cell proliferation, invasion, migration, and the percentage of G1-phase cells, while inhibiting apoptosis. ASCT2 silencing had the opposite effect. The expression of ASCT2 was negatively associated with NK cells in OC. ASCT2 overexpression in SKOV-3 cells led to excessive IL-17A/F production and inhibited the antitumor activity of NK cells, possibly through activating the IL-17 signaling pathway. The core regulatory genes c-JUN/PTGS2 in this pathway were upregulated, and antitumor cytokines were decreased in co-cultured NK cells, resulting in decreased antitumor activity and immune infiltration within the tumor. Our results suggest that overexpression of ASCT2 may play a predominant role in OC and NK cell immune infiltration within the tumor.

PGRN mediates the crosstalk between ovarian cancer cells and CAFs and reshapes tumor immune microenvironment

The tumor microenvironment (TME) serves crucial functions in ovarian cancer progression through complex interactions between tumor cells and stromal cells, particularly cancer-associated fibroblasts (CAFs). However, tumor-stroma interactions in ovarian cancer remain poorly characterized. Here, we identified progranulin (PGRN) as a key TME mediator that promotes crosstalk between tumor cells and CAFs, contributing to an immunosuppressive microenvironment. First, we discovered that PGRN deficiency in tumor cells attenuated malignant phenotypes and orthotopic tumor growth, while also suppressing CAF activation. Conversely, CAF-derived PGRN promoted tumor proliferation and invasion, while fibroblast-specific ablation of PGRN markedly suppressed tumor growth in vivo. Remarkably, PGRN in the TME rejected intratumoral CD8

The effectiveness of anti-PD-L1 treatment and the underlying regulatory mechanism in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) is typically associated with a poor prognosis. However, recent clinical trials have demonstrated that OCCC exhibits a nice response rate to immunotherapy. To identify whether anti-PD-L1 treatment was effective in OCCC and explore the underlying mechanism of the effectiveness. Western blot, real-time PCR, RNA Pull down protein mass spectrometry studies, and RIP experiments were accordingly used to detect ZFPM2-AS1/ HNRNPC/ PD-L1 axis at the level of molecular, cellular and animal experimental model, respectively. Flow cytometry analysis, the wound healing and transwell assay were conducted to detect the OCCC biological behaviors. In our study, we clearly identified the effectiveness of anti-PD-L1 treatment in OCCC, and found PD-L1 was highly expressed in OCCC and was closely related to the proliferation, invasion and metastasis in vitro and in vivo. In addition, ZFPM2-AS1 was also find overexpression in OCCC and could combine to HNRNPC, and ZFPM2-AS1/HNRNPC axis participated in regulating the effectiveness of anti-PD-L1 treatment. Our study provided a therapeutic regime that is urgently needed in OCCC and full of prospects.

F-box only protein 25-mediated α-actinin 1 upregulation drives ovarian cancer progression via ERK1/2 signaling in tumor cells and macrophage M2 polarization

ACTN1 belongs to the α-actinin family and is considered a tumor-promoting gene in various tumor types; however, the biological function and fundamental molecular mechanisms of ACTN1 in ovarian cancer remain unclear. The HPA and The Cancer Genome Atlas (TCGA) databases were used to compare the expression of ACTN1 in normal ovarian and OC tissues. The Kaplan-Meier Plotter database was used to analyze the relationship between the expression of ACTN1 and the prognosis of ovarian cancer. The TIMER2.0 database was used to analyze the correlation between the expression of ACTN1 and macrophages. CCK-8, colony formation, and Transwell assays as well as flow cytometry were used to determine the biological properties of the cells. Protein expression was assessed by immunohistochemistry, immunofluorescence, and western blot analysis. A co-culture experiment was used to analyze the effect of ovarian cancer cells on the polarization of macrophages. Co-immunoprecipitation was performed to validate the interaction between FBXO25 and ACTN1. ACTN1 was highly expressed in OC tissues and cell lines. Downregulation of ACTN1 attenuated the proliferation, migration, and invasion of OC cells, promoted apoptosis and reduced the aggregation of M2 macrophages and the expression of CD163. The opposite effect was observed following the upregulation of ACTN1. Mechanistically, ACTN1 knockdown reduced ERK1/2 phosphorylation and inhibited epithelial-mesenchymal transition (EMT), whereas its overexpression resulted in the opposite effect. The ERK1/2 inhibitor LY3214996 partially reversed cell proliferation, migration, and M2 polarization of macrophages promoted by ACTN1 overexpression. Moreover, FBXO25, which is upstream of ACTN1 and interacts with it. FBXO25 upregulation partially reversed cell proliferation and migration inhibited by ACTN1 knockdown. Upregulation of ACTN1 by FBXO25 promotes the progression of ovarian cancer by activating the ERK1/2 signaling pathway and M2 polarization of macrophages. The FBXO25/ACTN1/ERK1/2 axis and M2 macrophages may represent promising targets for developing ovarian cancer treatments.

Leveraging miRNA-mediated expression profiles to predict prognosis and identify distinct molecular subtypes in ovarian cancer: a multi-cohort study

Ovarian cancer (OV) remains the deadliest gynecological malignancy, with non-coding RNA-mediated transcriptomic deregulation significantly influencing its prognosis and heterogeneous progression. In this study, we prioritized miRNA-mediated gene expression profiles by identifying key negative correlations between miRNA-mRNA pairs. We developed a machine learning-based non-coding index (NCI), incorporating a four-gene signature (GAS1, GFPT2, ZFHX4, and KCNA1) to predict patient prognosis and therapeutic response. Validation across multiple datasets revealed that OV patients with higher NCI scores had significantly poorer survival outcomes and resistance to immunotherapy. Additionally, we established a four-class subtyping taxonomy through unsupervised clustering, validated in four independent datasets. The S1 and S3 subtypes were characterized by high NCI scores, abundant stromal and immune infiltration, with the S3 subtype exhibiting the worst survival. Conversely, the S2 subtype showed downregulation of immune response genes, while the S4 subtype displayed epithelial differentiation and favourable prognosis. Integrative analyses of bulk and single-cell transcriptomic data revealed that the S3 subtype had a significantly higher fibroblast proportion compared to other subtypes, whereas the S1 subtype was marked by high T cell content. Through ridge regression-based drug sensitivity analyses, we prioritized candidate therapeutics for each subtype. Notably, the S3 subtype demonstrated sensitivity to dasatinib but resistance to methotrexate. Finally, we developed a user-friendly Shiny-based website to facilitate the application of our prognostic and subtype classification models (https://jli-bioinfo.shinyapps.io/NCI_online/). This study establishes a critical prognostic marker and proposes a novel molecular classification framework grounded in miRNA-regulated gene expression profiles, advancing our understanding of the non-coding mechanisms driving OV heterogeneity.

Myc-mediated inhibition of HIF1a degradation promotes M2 macrophage polarization and impairs CD8 T cell function through lactic acid secretion in ovarian cancer

Ovarian cancer, the eleventh most prevalent cancer among women and a significant cause of cancer-related mortality, poses considerable challenges. While the Myc oncogene is implicated in diverse cancers, its impact on tumours expressing Myc during immune therapy processes remains enigmatic. Our study investigated Myc overexpression in a murine ovarian cancer cell line, focusing on alterations in HIF1a function. Seahorse experiments were utilized to validate metabolic shifts post-Myc overexpression. Moreover, we explored macrophage polarization and immunosuppressive potential following coculture with Myc-overexpressing tumour cells by employing Gpr132

Hyperactivity of the IL-33-ILC2s-IL-13-M-MDSCs axis promotes cervical cancer progression

The interleukin-33(IL-33) - group 2 innate lymphoid cells (ILC2s) - interleukin-13(IL-13) - monocytic myeloid-derived suppressor cells (M-MDSCs) axis plays a critical role in promoting immune evasion in tumors; however, its specific function in cervical cancer remains poorly understood. In this study, we observed that the proportion of IL-33-ILC2s-IL-13-M-MDSCs were significantly elevated in both cervical cancer patients and the subcutaneous U14 cervical cancer mouse model, compared to normal controls. Our results suggest that IL-33 stimulates ILC2s to secrete IL-13, which, in turn, regulates M-MDSCs to enhance their immune evasion capabilities. Notably, in vitro blockade of IL-33 and IL-13 partially restored the levels and functions of both ILC2s and M-MDSCs. In conclusion, these findings imply that the overactivation of the IL-33-ILC2s-IL-13-M-MDSCs axis may contribute to cervical cancer progression. However, further in vivo blockade studies are required to fully elucidate the precise mechanisms underlying this interaction and to assess its potential therapeutic implications for cervical cancer.

Disfunction of communication among immune cells in minimal-deviation adenocarcinoma of the cervix as an immunotherapeutic opportunity

Minimal deviation adenocarcinoma (MDA) of the uterine cervix, also referred to as malignant adenoma, is a rare subtype of cervical adenocarcinoma that exhibits histological characteristics resembling those of benign tumors, resulting in a low diagnostic rate and a lack of effective treatment options. The transcriptomic features of MDA at the single-cell resolution and within the tumor microenvironment (TME) remain unclear. In this study, we conducted single-cell transcriptomic analyses of MDA samples (Ca) and adjacent normal tissues (PCa). The present study reveals the prevalence of dendritic cells (DCs) and T cells in the carcinoma (Ca) of mammary ductal adenocarcinoma (MDA), with DCs undergoing significant metabolic reprogramming and immune stress. Additionally, our findings demonstrate the crucial involvement of DCs and T cells in the pathogenesis and metastatic progression of MDA, as evidenced by single-cell transcriptomic profiling of MDA and HPV samples. This resource provides a more profound understanding of the indolent nature of MDA and may prove useful in the development of MDA immunotherapy.

TMPRSS11D/ALR-mediated ER stress regulates the function of myeloid-derived suppressor cells in the cervical cancer microenvironment

Myeloid-derived suppressor cells (MDSCs) contribute to tumor immune evasion, and have been identified as immunosuppressive cells in cervical cancer. The effect of TMPRSS11D (transmembrane serine protease 11D) in some cancers has been reported, but its role in immune escape of cervical cancer is still unclear. This study aims to elucidate the regulatory mechanism of TMPRSS11D on the immunosuppressive function of MDSCs in cervical cancer. Our data showed that the proportion of polymorphonucleoid MDSCs (PMN-MDSCs), the contents of immunosuppressive factors (including INOS, IDO, and ARG-1) secreted by MDSCs, and TMPRSS11D mRNA level in peripheral blood mononuclear cells (PBMCs) of malignant cervical cancer patients was significantly higher than that of benign tumor patients. Next, CD3

Role of Cancer-Associated fibroblast in the pathogenesis of ovarian Cancer: Focus on the latest therapeutic approaches

Ovarian cancer (OC) is the seventh most common malignancy in women globally. This type of cancer can occur at any age, but it is more frequent in women over 50 and is usually diagnosed late. Despite platinum-based chemotherapy and optimal cytoreductive surgery, OC cells tend to metastasize, and patients with OC experience recurrent relapses and poor prognosis. Therefore, the emergence of novel therapies is essential for treating these patients. On the other hand, it has been shown that the tumor microenvironment (TME) and its components play an important role in the pathogenesis of OC. One of these components is cancer-associated fibroblast (CAF), which is involved in the growth and development of tumor cells by inducing tumor cells growth, proliferation, angiogenesis and inhibiting anti-tumor responses. Due to the importance of these cells in the TME, various therapeutic approaches such as direct targeting of CAFs, reprogramming of CAFs, and CAF-associated genes and molecules targeting have been suggested for OC treatment. This review summarizes the role of CAFs in the pathogenesis of OC and therapeutic approaches based on the mentioned therapeutic approaches.

Anti-pulmonary metastases from cervical cancer responses induced by a human papillomavirus peptide vaccine adjuvanted with CpG-oligodeoxynucleotides in vivo

Metastasis, particularly hematogenous metastasis, is associated with poor prognosis in patients with cervical cancer. The lungs are the most common site for hematogenous metastasis of cervical cancer. The currently available therapeutic modalities, including surgery, radiotherapy, or chemotherapy do not provide satisfactory clinical outcome for patients with pulmonary metastases. Therefore, it is necessary to investigate an alternative efficacious treatment modality. Therapeutic vaccines may evoke tumor-specific immune responses in patients to attack tumor cells, representing an attractive treatment option for controlling metastatic tumors. Our previous study demonstrated that a single administration of a human papillomavirus 16 E7 peptide vaccine, adjuvanted with unmethylated CpG-oligodeoxynucleotides, induced the clearance of subcutaneous xenograft cervical cancer. In this study, we investigated the anti-metastases responses induced by this vaccine using a murine model of pulmonary metastases from cervical cancer. The results showed that subcutaneous administration of the vaccine inhibited the growth of pulmonary metastases, which may be attributed to the increased infiltration of CD4 + and CD8 + T cells, and decreased number of immunosuppressive cells (including myeloid-derived suppressive cells and tumor-associated macrophages) in the lungs. Meanwhile, the alteration in a panel of cytokines, chemokines, and matrix metalloproteinases induced by the vaccination may contribute to the re-modulation of the local suppressive environment and inhibition of pulmonary metastases. To the best of our knowledge, this is the first report on the efficacy of the vaccine formula against murine pulmonary metastases from cervical cancer.

USP43 drives cervical carcinoma progression through regulation of the Hippo/TAZ pathway

Cervical carcinoma (CC) poses significant health challenges, with its pathogenesis not fully understood. While ubiquitin specific peptidase 43 (USP43) is implicated in various cancers, its role in CC and regulation of the Hippo/Transcriptional Co-Activator With PDZ-Binding Motif (TAZ) pathway remain unexplored. This study examines USP43's impact on CC progression and its interaction with TAZ. USP43 expression levels in CC tissues and cell lines were assessed using reverse transcription real-time polymerase chain reaction (RT-qPCR) and Western blot. The effects of USP43 silencing on cell proliferation, migration, and invasion were evaluated through cell counting Kit-8 (CCK-8), 5-ethynyl-2'deoxyuridine (EdU), colony formation, and transwell assays. Immunofluorescence staining and co-immunoprecipitation (Co-IP) assays were used to explore the interaction between USP43 and TAZ. Polyubiquitination assays were performed to evaluate ubiquitination and stability of TAZ, and cycloheximide (CHX) chase experiments determined the half-life of TAZ. In vivo studies using BALB/c nude mice examined the impact of USP43 knockdown on tumor growth and metastasis. USP43 was overexpressed in CC tissues and cell lines. Silencing of USP43 reduced cell proliferation, migration, invasion, and the epithelial-mesenchymal transition (EMT) process. Co-IP and ubiquitination assays revealed that USP43 interacted with and stabilized TAZ by inhibiting TAZ ubiquitination. CHX chase experiments confirmed that USP43 prolonged TAZ protein stability. In vivo, USP43 knockdown led to reduced tumor growth and lung metastasis. Overexpression of TAZ reversed the inhibitory effects of USP43 silencing on CC cell proliferation, migration, invasion and EMT CONCLUSION: USP43 promotes CC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) by activating the Hippo/TAZ pathway. These findings enhance our understanding of USP43's role in CC progression and highlight potential therapeutic targets for the treatment of CC.

Detection of association of IL1β, IL4R, and IL6 gene polymorphisms with cervical cancer in the Bangladeshi women by tetra-primer ARMS-PCR method

Cervical cancer (CC) is the main cause of cancer-related deaths among women in developing countries. It is the second leading female malignancy in Bangladesh in terms of incidence and mortality. Our present study aimed to investigate the association of IL1β (rs16944), IL4R (rs1801275), and IL6 (rs1800797) gene polymorphisms with the susceptibility of cervical cancer. This case-control study was conducted on 252 cervical cancer patients and 228 healthy volunteers, using tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). In the case of rs16944 polymorphism, GG genotype (OR = 2.10, 95%CI = 1.24-3.56), dominant model (OR = 1.71, 95% CI = 1.11-2.63), recessive model (OR = 1.54, 95% CI = 1.01-2.35), and G allele (OR = 1.30, 95% CI = 1.005-1.68) were significantly associated with increased cervical cancer risk. Among these, GG genotype and dominant model remained significant after the Bonferroni correction (p < 0.017). For rs1801275 polymorphism, GG genotype (OR = 2.66, 95% CI = 1.49-4.75), dominant model (OR = 1.49, 95% CI = 1.04-2.14), recessive model (OR = 2.45, 95% CI = 1.40-4.27), and G allele (OR = 1.59, 95% CI = 1.21-2.10) significantly elevated the risk of cervical cancer but significance did not exist for dominant model after the Bonferroni correction. rs1800797 variant showed significantly increased risk in all genetic models including, AG genotype (OR = 8.13, 95% CI = 5.27-12.55), AA genotype (OR = 9.86, 95% CI = 2.76-35.21), dominant model (OR = 8.25, 95% CI = 5.40-12.60), recessive model (OR = 4.41, 95% CI = 1.25-15.56), and A allele (OR = 4.99, 95% CI = 3.49-7.13) and the significances were consistent with the Bonferroni correction except recessive model. Haplotyping analysis indicates that GAA (p = 5.15x10 Our results conclude that rs16944 (IL1β), rs1801275 (IL4R), and rs1800797 (IL6) polymorphisms are associated with cervical cancer in Bangladeshi women.

m6A-modified circNFIX promotes ovarian cancer progression and immune escape via activating IL-6R/JAK1/STAT3 signaling by sponging miR-647

Ovarian cancer (OC) is one of the most common gynecological malignant cancers. Our previous work confirmed that circNFIX acted as an oncogene in OC, which could promote malignant proliferation, metastasis and angiogenesis. However, the role and mechanism of circNFIX in OC immune escape remain unclear. The RNA and protein levels were determined by qRT-PCR and western blot assays. The malignant phenotypes were tested by cell count kit-8, EdU staining, flow cytometry and transwell assays. The immune cytokines levels were measured by ELISA analysis. Molecular interactions were verified employing RNA immunoprecipitation, meRIP and dual luciferase methods. In vivo validation was performed by xenograft tumor and lung metastasis model. Hematoxylin & eosin and immunohistochemistry staining were used to observe the pathological changes. The levels of circNFIX, PD-L1, and IL-6R were upregulated in OC tissues and cell lines, while miR-647 was downregulated. Functional assays showed that loss of circNFIX suppressed the growth, metastasis and immune escape of OC cells both in vitro and in vivo. On the molecular level, the m6A modification of circNFIX was elevated in OC cells, and its expression was positively correlated to m6A modification and depended on IGF2BP1 ∼ 3 recognition. Moreover, circNFIX acted as a competing endogenous RNA for miR-647 to upregulate IL-6R expression, thereby activating JAK/STAT3 signaling and elevating PD-L1 expression. Rescue assays revealed that co-silencing of miR-647 reversed the antitumor effects of circNFIX knockdown on cell proliferation, metastasis and immune escape of OC cells. This study provided a comprehensive understanding of the molecular mechanism about circNFIX in OC, demonstrating m6A activated-circNFIX accelerated OC development and immune escape via regulating miR-647/IL-6R/PD-L1 pathway.

Association study of IL10 gene polymorphisms (rs1800872 and rs1800896) with cervical cancer in the Bangladeshi women

Cervical cancer is one of the most destructive diseases among females worldwide, especially in developing countries. Interleukin-10 (IL10) is a multifunctional cytokine, and polymorphisms in the IL10 gene have been identified in multiple malignancies. However, no prior studies were conducted to determine the association of IL10 polymorphisms (rs1800872 and rs1800896) with cervical cancer patients in Bangladesh. This case-control study was carried out on 240 cervical cancer patients and 204 healthy volunteers. Genotyping was performed using the tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR). In the case of rs1800872, CA and AA genotypes significantly increased the risk of cervical cancer (OR = 1.59, 95% CI = 1.01-2.49, p = 0.043; OR = 2.75, 95% CI = 1.53-4.93, p = 0.0007, respectively) but the significance did not exist for CA genotype after Bonferroni correction (p < 0.025). An increased risk was also observed for the dominant model, recessive model, and allele model (A vs. C) of rs1800872 (dominant model: OR = 1.83, 95% CI = 1.18-2.80, p = 0.006; recessive model: OR = 2.00, 95% CI = 1.22-3.29, p = 0.006; allele model: OR = 1.55, 95% CI = 1.19-2.03, p = 0.001) which remained significant after the correction of Bonferroni. For rs1800896, only GG genotype and recessive model showed increased risk for cervical cancer (GG vs. AA: OR = 3.48, 95% CI = 1.46-8.31, p = 0.005; recessive model: OR = 3.57, 95% CI = 1.52-8.38, p = 0.003). These associations were statistically significant, and the significance existed after Bonferroni correction. Haplotype analysis revealed that AA haplotype significantly increased the risk (OR = 1.56, p = 0.001) whereas, CA haplotype significantly lowered the risk (OR = 0.42, p = 2.42x10 Our study suggests that rs1800872 and rs1800896 polymorphisms of IL10 gene are associated with cervical cancer in Bangladeshi females.

Prognosis prediction signature of seven immune genes based on HPV status in cervical cancer

Cervical cancer (CC) has a high incidence and mortality rate, with a low 5-year survival rate, and human papillomavirus (HPV) is one of its carcinogenic risks. However, little evidence exists on the impact of HPV infection on the survival of patients with CC. In the present study, the CC cohort and immune genes were downloaded from the TCGA database and the ImmPort database, respectively. Subsequently, the Gene Set Enrichment Analysis was performed and found that HPV status was involved in multiple immune signaling pathways, which revealed that HPV infection might play critical roles in the immune response. Then seven prognostic immune genes were identified according to HPV status in CC. Using the seven immune genes, we established an immune risk score (IRS) signature and the Kaplan-Meier curve showed that high IRS was significantly correlated with poor prognosis of CC in both the training sets (HR = 2.32, 95% CI = 1.66-3.33; AUC = 0.712) and the validation sets (HR = 1.38, 95% CI = 1.02-1.85 and AUC = 0.583 in TCGA-HNSCC; HR = 2.58, 95% CI = 1.364-4.893, AUC = 0.676 in GSE44001). A nomogram of IRS combined with clinical features was established, and further analyses demonstrated that the power of the nomogram to predict the prognosis of CC was more reliable than that of a single independent factor. In conclusion, this study provided a more comprehensive understanding of the correlation between HPV and immune mechanisms as well as a novel signature that can effectively predict the prognosis of CC patients.

Polymorphisms and haplotypes of TLR4, TLR9 and CYP1A1 genes possibly interfere with high-risk human papillomavirus infection and cervical cancer susceptibility in Jharkhand, India

Expression and single nucleotide polymorphisms (SNPs) of TLR4/9 and CYP1A1 genes are vital for cervical squamous cell carcinoma (CSCC) but considerably vary in different populations. A total of 255-subjects from Jharkhand (130-cases, 125-controls) were utilized to obtain the expression/SNP status of TLR4/9, CYP1A1, and E6 (HPV16/18) by RT-PCR, WB, and allele-specific-PCR followed by sequencing. Over-expression of TLR4/9 and high infection of HPV16/18(78.5%) were found to be associated with CSCC. Among the seven SNPs(p1-p7) tested, the CT-genotype (p3:rs1927911; OR = 2.142; p = 0.004) and 'T'-allele (p3; OR = 1.694; p = 0.0061) of TLR4; CC-genotype (p4:rs5743836; OR = 3.307; p = 0.0018), 'C'-allele (p4; OR = 1.895; p = 0.0009), GA-genotype (p5:rs352140; OR = 2.064; p = 0.0172), AA-genotype (p5; OR = 2.602; p = 0.0021) and 'A'-allele (p5; OR = 1.939; p = 0.0002) of TLR9; and the TC-genotype (p6:rs4646903; OR = 1.967; p = 0.0452) and GG-genotype (p7:rs1048943; OR = 2.336; p = 0.0287) and 'G'-allele (p7; OR = 1.685; p = 0.0082) of CYP1A1 were associated with an increased-risk of CSCC. Similarly, the p3:CT-genotype (OR = 1.993; p = 0.0134); p4:CC-genotype (OR = 3.071; p = 0.0057) and 'C'-allele (OR = 1.838; p = 0.0029); p5:AA-genotype (OR = 2.231; p = 0.0147) and 'A'-allele (OR = 1.756; p = 0.0032); p6:TC-genotype (OR = 2.370; p = 0.02); and the p7:GG-genotype (OR = 2.255; p = 0.0488) and 'G'-allele (OR = 1.691; p = 0.0118) showed an association with HPV16/18 infection. Conversely, TLR4 (p1-p2-p3:A-G-T; OR = 3.361; p = 0.029), TLR9 (p4-p5:C-A; OR = 1.786; p = 0.032) and CYP1A1 (p6-p7:C-G; OR = 1.783; p = 0.033) haplotypes with CSCC susceptibility was observed, whereas the TLR4 (p1-p2-p3:A-C-C; OR = 0.4675; p = 8.E-3) and TLR9 (p4-p5:T-G; OR = 0.3937; p = 0.00) haplotypes showed protection against the development of CSCC. Further, though p1:rs10759931 and p2:rs11536889 were found to be insignificant, the p3:CT-genotype, p5:GA/AA-genotype, and p7:GG-genotype were associated with elevated protein; the p4:CC-genotype and p6:TC-genotype were associated with increased mRNA compared to their respective-wild-type-groups. The present study revealed an association between TLR4/9 and CYP1A1 polymorphisms with increased HPV16/18 infection susceptibility and CSCC risk among the women of Jharkhand state.

Construction of an immune-related gene signature for prediction of prognosis in patients with cervical cancer

Cervical cancer (CeCa) is becoming an intractable public health issue worldwide. Emerging evidence uncovers that the tumor progression and prognosis of patients with CeCa are tightly associated with the abundance of tumor-infiltrating immune cells. In the current study, the abundance of tumor-infiltrating immune cells in CeCa samples was assessed by using the ssGSEA, thereby generating two immune-related groups according to the immune status. A 4-gene prognostic signature (RIPOR2, DAAM2, SORBS1, and CXCL8) was next established based on the grouping and its predictive capability was validated by multiple analyses. The TIMER database was used to evaluate the association between 4 hub gene expression and immune cell infiltration. Immunophenoscore (IPS) was used to assess response to immune checkpoint inhibitors in CeCa samples. As the results, a novel grouping strategy based on immune cell infiltration was developed and validated. Based on the grouping, a 4-gene signature was identified to be an independent prognostic indicator for overall survival (OS) in CeCa patients. Among the 4 hub genes, RIPOR2 and CXCL8 expression were significantly correlated with immune cell infiltration. Besides, higher immune checkpoints expression and IPS scores were found in the 4-gene signature low-risk group, suggesting a more immunoactive status that tended to respond to immune checkpoint inhibitors. To sum up, a novel immune-related signature is established to predict CeCa patients' prognosis and also associated with response to immune checkpoint inhibitors, which might be a promising prognostic stratification strategy and innovate therapeutic management.

A prognostic signature based on immune-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the fourth commonest female malignancy worldwide. CESC progresses in immune-microenvironment mainly composed of infiltrating immune and stromal cells. Here, we performed an integrated analysis incorporating the expression profiles from the Cancer Genome Atlas (TCGA) database and scores of immune and stromal cells calculated by Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm. A two-gene signature (CD1C and CD6 genes) was established to predict the prognosis of CESC. Based on this signature, patients were divided into the high- and low-risk groups, and this signature showed good prognostic performance according to the results of Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis in train set and two validation sets. A nomogram was built for evaluating the clinical applicability of this signature. In addition, based on Tumor Immune Estimation Resource (TIMER) database, 2 hub genes showed negative correlations with tumor purity and positive correlations with infiltrating levels of immune filtrating cells. What's more, we propose new treatment strategies for the two prognostic subtypes. Low- risk patients were found presenting with a higher level of immune checkpoint molecules and showing higher immunogenicity in immunophenoscore (IPS) analysis, which indicated a better response for immunotherapy. Meanwhile, estimated by Genomics of Drug Sensitivity in Cancer (GDSC) database, the high-risk patients showed sensitive responses to five chemotherapy drugs. Finally, 10 candidate small-molecule drugs for CESC were defined. In summary, the CD1C-CD6 signature can accurately predict the prognosis of CESC.

Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo

The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer.

An update on existing therapeutic options and status of novel anti-metastatic agents in breast cancer: Elucidating the molecular mechanisms underlying the pleiotropic action of Withania somnifera (Indian ginseng) in breast cancer attenuation

Downregulation of ATP5F1D inhibits mtROS/NLRP3/caspase-1/GSDMD axis to suppress pyroptosis-mediated malignant progression of endometrial cancer

In developed countries, endometrial cancer (EC) is the most prevalent gynecological cancer and its occurrence is associated with chronic inflammation. ATP5F1D is a subunit of ATP synthase (complex V), as well as the important component of mitochondrial electron transport chain (ETC). ETC play compelling roles in carcinogenesis. To date, little is known about the role of ATP5F1D in EC. ATP5F1D expression was identified in EC tissues and EC cell lines. We evaluated the influence of ATP5F1D on clinical features and prognosis based on TCGA database. The effects of ATP5F1D in EC malignant progression by applying loss-of-function assays in KLE and Ishikawa cell lines were detected by EdU, CCK-8, wound healing, Transwell, and flow cytometry assays. Additionally, electron microscope, LDH release, ELISA, mitochondrial ROS measurement, and Immunofluorescence were performed to demonstrate ATP5F1D can affect the pyroptosis of EC. To observe the anti-tumor effect on ATP5F1D silencing, we established an in vivo human endometrial tumor model using nude mice. ATP5F1D expression was significantly upregulated in EC and was associated with favorable prognosis. ATP5F1D knockdown inhibited the proliferation, invasion, and migration of EC cells. Similarly, in nude mice, ATP5F1D knockdown suppressed the growth EC cells. Knocking down ATP5F1D lead to decrease the production of mitochondrial ROS (mtROS) and inhibited pyroptosis of EC cells. Downregulation of ATP5F1D as a new therapeutic strategy that could mediate pyroptosis via suppressing mtROS/NLRP3/caspase-1/GSDMD pathway to inhibit EC progression.

The key role of natural products in the fight against endometrial Cancer

Endometrial cancer (EC) is a common malignant disease in women, originating from the endometrial tissue. Over the past few decades, the global incidence rate of EC has gradually increased, and the affected population has become progressively younger. Traditional treatment methods, such as surgery and adjuvant therapy, have considerable toxic side effects. Furthermore, their therapeutic effectiveness is significantly very uncertain. Therefore, the search for a new type of treatment for EC is a top priority. Natural products are a class of compounds found in nature that have a wide range of biological functions; their derivatives have chemical structures that show great potential for developing new drugs. The latest studies have found that certain natural products, such as flavonoids, plant polyphenols, terpenoids and alkaloids, have inhibitory effects on EC cells in non-clinical models and animal studies. Despite challenges, including low extraction and bioavail ability, the potential of natural products for treating EC is still highly regarded by the scientific community. In the future, as research on natural products deepens and is combined with modern drug design and delivery technologies, it is hoped that more efficient and less toxic anti-cancer drugs will be developed, thereby offering EC patients more treatment options and hope. This article summarises the possible molecular mechanisms of various natural products and their bioactive components with regard to EC cells, as well as the latest research, to provide new ideas for further research and drug development.

A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets in Uterine Corpus Endometrial cancer

Adhesion G protein-coupled receptors (adhesion GPCRs), as a member of the G protein-coupled receptors (GPCRs) superfamily, have gradually entered the field of vision of researchers. The structure, function, and involvement of adhesion GPCRs in cancer development have been discussed in a series of papers. Uterine Corpus Endometrial Carcinoma (UCEC) isa malignanttumorofendometrium epithelial, whichis alsooneofthemostcommonfemalereproductivesystemtumors, but there are few pieces of research related to adhesion GPCRs in UCEC. In the current study, the UALCAN, GEPIA, Kaplan-Meier Plotter, MethSurv, SurvivalMeth, cBioPortal, String, GeneMANIA, DAVID, TRRUST, and Timer databases were used to examine the expression patterns and probable roles of adhesion GPCR family in UCEC. The expression levels of ADGRC1, ADGRC3, ADGRE1, ADGRF1, ADGRF2, ADGRF3, ADGRF4, ADGRG1, ADGRG5, ADGRG7, and ADGRV1 were significantly elevated in UCEC tissues, and the expression of ADGRC3 and ADGRF1 was significantly correlated with the pathological stage of UCEC. In patients with UCEC, ADGRA3, ADGRB1, ADGRB2, ADGRB3, ADGRC3, ADGRD2, ADGRF1, ADGRF2, ADGRF4, ADGRG1, ADGRG2, ADGRG4, ADGRG6, ADGRG7, ADGRL1, ADGRL2, and ADGRL3 had played important roles in patients' overall survival (OS), with a high expression suggesting shorter OS; while high levels of ADGRC2, ADGRD2, ADGRG7, and ADGRL2 suggested lower relapse-freesurvival (RFS). Furthermore, the prognostic value of the adhesion GPCRs gene individual CpG, as well as DNA methylation, was also analyzed; however, DNA methylation profiling demonstrated no significant correlation between the methylation level of adhesion GPCRs and the prognosis. The neighbor gene interaction analysis and enrichment analysis were also implemented to detect the possible mechanism. In addition, we found a correlation between the adhesion GPCRs and immune infiltrating cells, and the Cox proportional risk model of adhesion GPCRs with six immune cells showed that ADGRA1, ADGRF1, and ADGRG3 were closely connected with the clinical manifestations of UCEC patients. The adhesion GPCRs, especially ADGRF1, might be used as immunotherapeutic targets and prognostic markers of UCEC.

Artesunate-induced ATG5-related autophagy enhances the cytotoxicity of NK92 cells on endometrial cancer cells via interactions between CD155 and CD226/TIGIT

Uterine corpus endometrial carcinoma (UCEC) is the most prevalent gynecologic cancer in developed countries and lacks efficient therapeutic strategies. Artesunate (ART), a well-modified derivate of artemisinin, exerts potent anti-cancer effects apart from its classical anti-malaria feature. Autophagy is a universal double-edged process in cell survival, and CD155 is a novel immune checkpoint highly expressed in numerous cancers. However, the relationships among ART, autophagy, and CD155 remain unclear in UCEC. In this study, we discovered that ART not only inhibited proliferation and migration, promoted apoptosis, but also induced autophagy in UCEC cells. Meanwhile, ART-induced autophagy elevated the level of CD155 in UCEC cells, thereby enhancing the cytotoxicity of natural killer cell line (NK92) by modulating the interactions between CD155 and its receptors in NK92 cells via upregulation of co-stimulator CD226 and downregulation of co-inhibitor TIGIT. Additionally, ART regulated CD155 partially via ATG5, and knockdown of ATG5 dampened the expression of CD155 in UCEC cells, thus decreasing the cytotoxicity of NK92 cells. Therefore, this study demonstrated the dual anti-cancer effects of ART as it could induce cell-killing directly and indirectly, which provides novel insights into the anti-cancer mechanisms of ART on UCEC.

Identification of prognostic and immune-related gene signatures in the tumor microenvironment of endometrial cancer

Uterine corpus endometrial cancer (UCEC) is one of the most prevalent female malignancies in clinical practice. Due to the lack of effective biomarkers and personalized treatments, the prognosis of advanced-stage EC remains unfavorable. Modulation of the immune microenvironment is closely related to the onset and development of endometrial cancer. In the present study, we attempt to systematically analyze the characteristics of the immune microenvironment of endometrial cancer and investigate its association with clinical features by applying bioinformatics. RNA-Seq in TCGA (The Cancer Genome Atlas) and clinical follow-up information of patents were used for analysis. The Tumor Microenvironment (TME) score infiltration patterns of 523 endometrial cancer patients were evaluated using CIBERSORT. Random forest, multivariable cox analysis were used to build the TME score. Fisher's exact test was used to compare the genes that show significant differences in the frequency of mutations between groups. Two TME phenotypes were defined. There is a significant relationship between the TME score and grade. High TME score samples are highly expressed in immune activation, TGF pathway activation and immune checkpoint genes, and low TME score samples have high frequency mutations of PTEN, CSE1L and ITGB3. Therefore, describing the comprehensive landscape of UCEC's TME characteristics may help explain patients' response to immunotherapy and provide new strategies for cancer treatment.