Background: Ovarian cancer (OC) remains the most common cause of gynecological cancer-related death, and about 70% of these deaths are from advanced high-grade serous ovarian cancer (HGSOC). Cysteine-rich secretory protein 3 (CRISP3) is related to various human diseases; however, the roles and mechanisms of CRISP3 in HGSOC remain unclear. Methods: The clinical significance of CRISP3 in patients with OC was analyzed using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. CRISP3 expression in OC tissues was validated by RNA-sequencing (RNA-seq), quantitative PCR, and immunohistochemistry. Furthermore, we explored the effect of CRISP3 expression modulation on the biological behavior of HGSOC through CCK-8, EdU, and Transwell assays in vitro, and the differences in CRISP3 during the progression of HGSOC in vivo. We utilized RNA-seq, GSEA and Western blotting to detect CRISP3’s regulatory mechanisms. Finally, we employed data from the IMvigor210 cohort and TCGA to assess the correlation of CRISP3 with clinical response to immunotherapy, and the landscape of immune cell infiltration. Results: CRISP3 expression was markedly reduced in HGSOC. In vitro studies demonstrated that CRISP3 knockdown significantly enhanced proliferation, migration, and invasion of HGSOC cells, whereas its overexpression suppressed these malignant phenotypes. Moreover, CRISP3 expression was found to be downregulated during OC progression in vivo. Mechanistically, CRISP3 acted as a tumor suppressor through the PI3K/AKT signaling pathway to inhibit the progression and metastasis of HGSOC. Additionally, we observed an association between CRISP3 expression and CD8⁺ T cell, macrophage, neutrophil and Th1 cell infiltration. Conclusions: We demonstrate that CRISP3 suppresses tumorigenesis in HGSOC by regulating the PI3K/AKT pathway, and that alterations in its expression correlate with disease progression, supporting its utility as a biomarker.

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer, but resistance and recurrence remain major clinical challenges. Tumor immune–metabolic reprogramming profoundly affects treatment response and immune evasion; however, the molecular mechanisms of lipid metabolism remodeling and its interaction with T cells after CCRT in cervical cancer are still unclear. This study aimed to investigate how CCRT-induced metabolic changes in cervical cancer cells influence T cell function and immune evasion. Methods: We performed metabolic pathway activity analysis, cell–cell communication prediction, and transcriptomic analysis on paired single-cell transcriptomic data from three cervical cancer patients before and after CCRT (n = 3 paired). Validation was conducted using multiple independent GEO cohorts, in vitro cell culture experiments, and multi-sample immunofluorescence staining. Results: CCRT was associated with upregulation of FABP4/5 in malignant epithelial cells and activation of the PPAR and adipocytokine signaling pathways, leading to lipid metabolic reprogramming. Epithelial cells with high FABP4/5 expression showed enhanced predicted intercellular communication with T cells via the computationally inferred ligand–receptor axes PTGER4 and CXCR4. T cells with high communication intensity exhibited an immunosuppressive phenotype signature, accompanied by metabolic alterations in lipid and carbohydrate pathways and enrichment of regulatory T cell subsets. Validation experiments confirmed the association between FABP4/5 and inhibitory T cells. Conclusions: This study suggests that FABP4/5-mediated lipid metabolism reprogramming may represent a key mechanism contributing to the immunosuppressive crosstalk between cervical cancer epithelial cells and T cells after CCRT. Targeting this axis may reverse T cell dysfunction and provide a potential immunometabolic strategy to reduce post-CCRT recurrence.