Jinwei Miao

Immunotherapy for Ovarian Cancer: Disappointing or Promising?

Ovarian cancer, one of the deadliest malignancies, lacks effective treatment, despite advancements in surgical techniques and chemotherapy. Thus, new therapeutic approaches are imperative to improving treatment outcomes. Immunotherapy, which has demonstrated considerable success in managing various cancers, has already found its place in clinical practice. This review aims to provide an overview of ovarian tumor immunotherapy, including its basics, key strategies, and clinical research data supporting its potential. In particular, this discussion highlights promising strategies such as checkpoint inhibitors, vaccines, and pericyte transfer, both individually and in combination. However, the advancement of new immunotherapies necessitates large controlled randomized trials, which will undoubtedly shape the future of ovarian cancer treatment.

Small‐molecule inhibitor HI‐TOPK‐032 improves NK‐92MI cell infiltration into ovarian tumours

AbstractThe effectiveness of natural killer (NK) cells transferred adoptively in combating solid tumours is limited by challenges such as their difficulty in penetrating tumours from the bloodstream and maintaining viability without the support of interleukin‐2 (IL‐2). Genetically modified NK‐92MI cells, which can release IL‐2 to sustain their viability, have been identified as a promising alternative. This adaptation addresses the negative consequences of systemic IL‐2 administration. The role of PSD‐95/discs large/ZO‐1 (PDZ)‐binding kinase (PBK) in cancer development is recognized, but its effects on immunity are not fully understood. This study explores how PBK expression influences the ability of NK‐92MI cells to infiltrate ovarian tumours. Elevated levels of PBK expression have been found in various cancers, including ovarian cancer (OV), with analyses showing higher PBK mRNA levels in tumour tissues compared to normal ones. Immunohistochemistry has confirmed increased PBK expression in OV tissues. Investigations into PBK's role in immune regulation reveal its association with immune cell infiltration, indicating a potentially compromised immune environment in OV with high PBK expression. The small‐molecule inhibitor HI‐TOPK‐032, which inhibits PBK, enhances the cytotoxicity of NK‐92MI cells toward OV cells. It increases the production of interferon‐γ and tumour necrosis factor‐α, reduces apoptosis and encourages cell proliferation. Mechanistic studies showed that contact with OV cells treated with HI‐TOPK‐032 upregulates CD107a on NK‐92 cells. In vivo studies demonstrated that HI‐TOPK‐032 improves the antitumour effects of NK‐92MI cells in OVCAR3Luc xenografts, extending survival without significant side effects. Safety assessments in mice confirm HI‐TOPK‐032's favourable safety profile, highlighting its potential as a viable antitumour therapy. These results suggest that combining NK‐92MI cells with HI‐TOPK‐032 enhances antitumour effectiveness against OV, indicating a promising, safe and effective treatment strategy that warrants further clinical investigation.

B7-H3-mediated reversal of CAR-T cell exhaustion induces a notable antitumour response in ovarian cancer models

Functional CAR-T cell exhaustion in the immunosuppressive tumour microenvironment remains the main barrier to the success of CAR-T cell therapy for treating solid tumours. Mesothelin (MSLN) has emerged as an attractive target for CAR-T cell therapy for several solid malignancies, including ovarian cancer. In this study, we aimed to investigate the role and mechanism of lipid metabolites in anti-MSLN CAR-T cell exhaustion in ovarian cancer cells. We engineered anti-MSLN CAR-T cells targeting ovarian cancer cells with high MSLN expression as a pivotal tool for in vitro and in vivo experiments. Moreover, liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed the critical role of oxylipin 12-HETE in the exhaustion of CAR-T cells. By employing structure-based high-throughput virtual screening (HTVS), we identified the inhibitor targeting B7-H3. We demonstrated that GPR31-dependent 12-HETE accumulation in the ovarian cancer microenvironment drives CAR-T cell exhaustion via lipid peroxidation, impairing their antitumour efficacy. Genetic or pharmacological inhibition of the 12-HETE/GPR31 axis restored CAR-T cell cytotoxicity and proliferation, leading to significant tumour regression in murine models. Silencing B7-H3 relieved repression of FOXO3, leading to reduced 12-LOX expression and lower 12-HETE levels, which places B7-H3 upstream of this metabolic checkpoint. Through structure-based screening, we identified HI-TOPK-032 as a potent B7-H3 inhibitor that synergised with CAR-T cell therapy by reversing exhaustion markers (e.g., PD-1, TIM-3) and enhancing cytokine polyfunctionality. Combined HI-TOPK-032 and anti-PD-1 treatment achieved superior tumour control compared to monotherapies, particularly in B7-H3/12-LOX-high patient-derived xenografts, underscoring its precision therapeutic potential. CAR-T cell therapy combined with HI-TOPK-032 is a promising novel strategy for treating MSLN-expressing solid tumours. This study was funded by the National Natural Science Foundation of China (Grant number: 82503173), Beijing Hospitals Authority's Ascent Plan (Grant number: DFL20221201), Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (Grant number: ZYLX202120), Beijing Natural Science Foundation (Grant number: 7162063), Capital Medical University Laboratory for Clinical Medicine and Gynecological Tumour Precise Diagnosis and Treatment Innovation Studio.

The accuracy of DNA methylation detection in endometrial cancer screening: A systematic review and meta‐analysis

AbstractObjectiveDNA methylation is the hallmark of early endometrial cancer and can be detected through non‐invasive methods. The present study systematically reviewed the efficacy of DNA methylation detection for endometrial cancer screening through exfoliative cytology.MethodsA systematic literature review was performed through the following databases from inception to October 7, 2024: PubMed, Embase, and the Cochrane Library. Studies on DNA methylation detection for endometrial cancer screening through exfoliative cytology were included. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The relevant variables included cytologic sample type, methylated genes, and marker performance (i.e., AUC value, sensitivity, specificity, and the corresponding 95% confidence interval [CI]), as well as the bias risk assessment according to the Cochrane Collaboration tool (Cochrane Intervention Systematic Review Guide 5.1.0).ResultsA total of 31 genes were selected from 20 studies as methylation markers for endometrial cancer detection in cytologic specimens. A total of 19 methylation markers for endometrial cancer detection with an area under the curve value from 0.80 to 0.97 were selected from 10 studies.ConclusionCytology‐based DNA methylation markers are feasible and accurate non‐invasive methods for the early detection of endometrial cancer screening in high‐risk populations.

A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer

The chromatin-modifying enzyme ATAD2 confers oncogenic competence and proliferative advantage in malignances. We previously identified ATAD2 as a marker and driver of cell proliferation in ovarian cancer (OC); however, the mechanisms whereby ATAD2 is regulated and involved in cell proliferation are still unclear. Here, we disclose that ATAD2 displays a classical G2/M gene signature, functioning to facilitate mitotic progression. ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. ChIP-seq data analyses demonstrated that DREAM and MYBL2-MuvB (MMB), two switchable MuvB-based complexes, bind the CHR elements in the ATAD2 promoter, representing a typical feature and principle mechanism of the periodic regulation of G2/M genes. As a downstream target of MYBL2, ATAD2 deletion significantly impaired MYBL2-driven cell proliferation. Intriguingly, ATAD2 silencing also fed back to destabilize the MYBL2 protein. The significant coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels highlights the existence of the MYBL2-ATAD2 signaling in OC patients. This signaling is activated during tumorigenesis and correlated with TP53 mutation, and its hyperactivation was found especially in high-grade serous and drug-resistant OCs. Disrupting this signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model, while pharmacologically targeting this signaling with an ATAD2 inhibitor demonstrated high therapeutic efficacy in both drug-sensitive and drug-resistant OC cells. Collectively, we identified a novel MYBL2-ATAD2 proliferative signaling axis and highlighted its potential application in developing new therapeutic strategies, especially for high-grade serous and drug-resistant OCs.

AI-driven patient-centered care: A digital transformation framework for gynecologic cancer genetic counseling

Objectives This study evaluates artificial intelligence (AI) reasoning capabilities in gynecologic cancer genetic counseling, comparing the performance of ChatGPT and DeepSeek models to guide patient-centered AI implementation in clinical genetics. Methods Using 40 National Comprehensive Cancer Network-aligned counseling scenarios, we conducted blinded dual-oncologist evaluations of two large language models. Methodological rigor included model anonymization, a pre-calibrated scoring framework, and validated metrics (Global Quality Scale and Patient Education Materials Assessment Tool) assessing informational coherence, understandability, and actionability. Results DeepSeek demonstrated superior informational breadth (mean character difference: −609.0, p  < .0001) and visual communication (diagram integration, p  < .01), with 49-fold greater probability in recommending clear and actionable actions ( p  < .01, OR = 49.0). ChatGPT excelled in concise summarization (22% faster response generation, p  = .013). Conclusion Strategic AI model selection—leveraging DeepSeek's visually-rich, structured educational approach for complex information, and ChatGPT's concise, rapid summarization for efficient communication—enhances patient-centered genetic education when combined with clinician oversight. This framework supports healthcare's digital transformation by optimizing human-AI collaboration in hereditary cancer care.

The prognostic significance of primary tumor site in vulvar cancer: a population-based cohort study

To investigate the association of primary tumor site with prognosis in vulvar cancer, stratified by vulvar squamous cell carcinoma (SCC) and non-SCC histological types. This population-based retrospective study enrolled patients with vulvar cancer from the Surveillance, Epidemiology, and End Results database between January 2000 and December 2018. The primary outcome was cancer-specific survival (CSS). The prognostic difference between labium majus, labium minus and clitoris groups was investigated using Kaplan-Meier analyses and Cox proportional hazards regression analyses. A total of 3,465 eligible patients with vulvar cancer were included with a mean age of 54.5 years. Among the 1,076 (31.1%) patients with non-SCC, the multivariate Cox regression analyses showed that labium minus-sited disease (hazard ratio [HR]=1.85; 95% confidence interval [CI]=1.27-2.71; p=0.001) and clitoris-sited disease (HR=2.37; 95% CI=1.47-3.85; p0.05). Kaplan-Meier analyses also showed that the primary tumor site had a significant prognostic effect in vulvar non-SCC (p<0.001) but not in vulvar SCC (p=0.330). Among vulvar non-SCC, patients with labium minus-sited disease had a significantly worse prognosis than those with labium majus-sited disease, and a significantly better prognosis than those with clitoris-sited disease. Gynecologic oncologists should consider the prognostic effect of primary tumor site in vulvar non-SCC, and make optimal, personalized treatment and surveillance strategies based on different primary tumor sites.