Hongbing Cai

LAG3 as a Tumor Suppressor and Immune Regulator in Cervical Cancer: From Functional Validation to Therapeutic Strategy

ABSTRACT Background Cervical cancer remains a significant health burden for women worldwide, with persistent high‐risk HPV infection being a major etiological factor. Despite treatment advances, prognosis for recurrent or metastatic disease remains poor. Pyroptosis, a form of programmed cell death, plays a dual role in tumor immunity, but its implications in cervical cancer are not fully elucidated. This study aims to systematically characterize pyroptosis‐related genes (PRGs) in cervical cancer and explore their prognostic and therapeutic relevance. Methods Multi‐omics data from TCGA and GEO databases were integrated to analyze genetic variations, expression patterns, and prognostic significance of 52 PRGs in cervical cancer. Consensus clustering was used to identify PRG subtypes. A prognostic risk score model was constructed using LASSO‐Cox regression based on differentially expressed genes (DEGs). Functional validation was performed via in vitro and in vivo experiments, including Western blot, CCK‐8, colony formation, transwell assays, and a subcutaneous tumor model. Single‐cell RNA sequencing data (GSE171894, GSE168652) were analyzed to explore LAG3 expression in the tumor immune microenvironment. Results Two distinct PRG subtypes were identified, with subtype A showing immune activation features. A five‐gene prognostic signature (GNAZ, LAG3, IL‐1β, CA2, SPRR3) effectively stratified patients into high‐ and low‐risk groups. Low LAG3 expression was associated with poor prognosis. Functional experiments demonstrated that LAG3 overexpression suppressed cervical cancer cell proliferation, migration, and tumor growth, while its knockdown promoted malignant phenotypes. Single‐cell analysis revealed high LAG3 expression in Treg and CD8⁺ T cells, suggesting its role in immune regulation. Conclusion This study establishes a novel PRG‐based prognostic model and highlights LAG3 as a key tumor suppressor and immune regulator in cervical cancer. These findings provide insights into the interplay between pyroptosis and antitumor immunity, supporting LAG3 as a potential therapeutic target for cervical cancer immunotherapy.

BAG2 Inhibits Cervical Cancer Progression by Modulating Type I Interferon Signaling through Stabilizing STING

Abstract Cervical cancer possesses high morbidity and mortality rates, and a comprehensive understanding of its molecular underpinnings is essential for advancing clinical management strategies. The innate immune sensor STING, which activates type I interferon signaling, plays a pivotal role in enhancing anti‐tumor activity. Despite increased attention to STING's involvement in cervical cancer, the regulatory mechanisms governing its protein homeostasis remain poorly understood. In this study, it is found that the BAG2‐STUB1 complex regulates ubiquitin proteasomal degradation of STING, which affects the development of cervical cancer. Mechanistically, BAG2 inhibits ubiquitination of STING and stabilizes it by interacting with STING. Specifically, BAG2 inhibits STUB1 from attaching the K48‐linked ubiquitin chains at K338 and K370 of STING by forming a complex with STUB1. Functionally, enhanced BAG2 expression suppresses cervical cancer progression by activating the type I interferon pathway in a STING‐dependent manner. Notably, clinical cervical cancer samples revealed a positive correlation between BAG2 and STING levels, with low BAG2 expression is strongly linked to advanced disease and poor prognosis in cervical cancer. Collectively, these findings elucidate the molecular mechanism by which the BAG2‐STUB1 complex regulates STING homeostasis, underscoring BAG2's potential as a diagnostic biomarker and therapeutic target in cervical cancer.

IFI16 promotes cervical cancer progression by upregulating PD-L1 in immunomicroenvironment through STING-TBK1-NF-kB pathway

Cervical cancer remains one of the leading causes of cancer death worldwide. Immunotherapy is the most promising cancer therapeutics in recent years and has gain positive results in several cancers in the clinic. This study was aimed to investigate the roles and mechanism of IFI16 in cervical cancer immunotherapy. We observed an abnormally high expression of Programmed cell death 1 ligand 1 (PD-L1) and Interferon-inducible 16 (IFI16) in Human papillomavirus (HPV) positive cervical cancer cells compared with HPV negative cervical cancer cells. Moreover, IFI16 promotes cervical cancer development in vitro and in vivo as the oncogenic role of PD-L1. In the subsequent mechanism investigation, we found that IFI16 activated STING-TBK1-mediated immunoregulation, and subsequently activated downstream NF-kB pathway, which interacted with the proximal region of PD-L1 promoter to facilitate PD-L1 expression. In conclusion, we found that IFI16 positively regulate PD-L1 through STING-TBK1-NF-kB pathway, thus promoting cervical cancer progression. The roles of IFI16 in cervical cancer progression deserve further investigation and hold the promise of being developed as a novel immunotherapy target in the future.

Systematic Construction and Validation of a Novel Ferroptosis-Related Gene Model for Predicting Prognosis in Cervical Cancer

Background and Purpose. Ferroptosis, a mechanism of cell death that is iron-dependent, participates in various pathologies of cancer (CC). Nevertheless, the specific function that ferroptosis plays in the onset and progression of cervical cancer (CC) is yet uncertain. This research sought to examine the value of ferroptosis-related genes (FRGs) in the progression and prognosis of CC. Methods. Datasets containing RNA sequencing and corresponding clinical data of cervical cancer patients were obtained from searching publicly accessible databases. The “NMF” R package was conducted to calculate the matrix of the screened prognosis gene expression. Ferroptosis-related differential genes in cervical cancer were detected using the “limma” R function and WGCNA. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis were conducted to develop a novel prognostic signature. The prediction model was verified by the nomogram integrating clinical characteristics; the GSE44001 dataset was used as an external verification. Then, the immune status and tumor mutation load were explored. Finally, immunohistochemistry as well as quantitative polymerase chain reaction (RT-qPCR) was utilized to ascertain the expression of FRGs. Results. Two molecular subgroups (cluster 1 and cluster 2) with different FRG expression patterns were recognized. A ferroptosis-related model based on 4 genes (VEGFA, CA9, DERL3, and RNF130) was developed through TCGA database to identify the unfavorable prognosis cases. Patients in cluster 1 showed significantly decreased overall survival in contrast with those in cluster 2 ( P < 0.05 ). The LASSO technique and Cox regression analysis were both utilized to establish the independence of the prognostic model. The validity of nomogram prognostic predictions has been well demonstrated for 3- and 5-year survival in both internal and external data validation cohorts. These two subgroups showed striking differences in tumor-infiltrating leukocytes and tumor mutation burden. The low-risk subgroup showed a longer overall survival time with a higher immune cell score and higher tumor mutation rate. Gene functional enrichment analyses revealed predominant enrichment in various tumor-associated signaling pathways. Finally, the expression of each gene was confirmed by immunohistochemistry and RT-qPCR. Conclusion. A novel and comprehensive ferroptosis-related gene model was proposed for cervical cancer which was capable of distinguishing the patients independently with high risk for poor survival, and targeting ferroptosis may represent a promising approach for the treatment of CC.

Cadonilimab Combined with Chemotherapy with or without Bevacizumab as First-Line Treatment in Recurrent or Metastatic Cervical Cancer (COMPASSION-13): A Phase 2 Study

Abstract Purpose: Immune checkpoint inhibitors (ICI) have been a potential treatment option for patients with cervical cancer in several clinical studies. We investigated the safety and efficacy of cadonilimab, a bispecific antibody targeting PD-1 and CTLA-4, plus standard therapy for the first-line treatment of R/M CC (recurrent and/or metastatic cervical cancer). Patients and Methods: Eligible patients were assigned to 3 cohorts: cohort A-15 (cadonilimab 15 mg/kg every 3 weeks (Q3W) plus chemotherapy), cohort A-10 (cadonilimb 10 mg/kg Q3W plus chemotherapy), and cohort B-10 (cadonilimab 10 mg/kg Q3W plus chemotherapy and bevacizumab). They received the corresponding treatments until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. The primary objective was safety; the secondary endpoints included objective overall response (ORR), duration of response, disease control rate, progression-free survival, and overall survival. This study is registered with ClinicalTrials.gov (NCT04868708). Results: As of February 13, 2023, treatment-related adverse events (TRAE) occurred in 45 (100.0%) patients. Grade ≥3 TRAEs were reported in 33 (73.3%) patients. Immune-related adverse events (irAE) occurred in 29 (64.4%) patients and grade ≥3 irAEs were observed in 9 (20.0%) patients. Seven (15.6%) of 45 patients permanently discontinued cadonilimab treatment due to TRAEs. One death due to hemorrhagic shock occurred in cohort B-10. Among 44 patients who underwent at least one post-baseline tumor assessment, the ORR was 66.7% in cohort A-15, 68.8% in cohort A-10, 92.3% in cohort B-10, and 79.3% in cohorts A-10 and B-10 combined. Conclusions: Cadonilimab combined with standard therapy was acceptable, with encouraging antitumor activity in patients with R/M CC.