Cell-intrinsic and tumor microenvironmental determinants of platinum resistance in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, primarily due to late-stage diagnosis, high relapse rates, and the inevitable emergence of platinum resistance. Although platinum-based chemotherapy produces high initial response rates, over 70% of patients eventually relapse with tumors that are refractory to treatment. Platinum resistance develops through complex and dynamic mechanisms involving both tumor-intrinsic and tumor-extrinsic factors. Tumor-intrinsic pathways include enhanced DNA repair, apoptosis evasion, metabolic reprogramming, and transcriptional or epigenetic plasticity, while tumor microenvironmental influences such as hypoxia, immune suppression, and stromal remodeling further sustain resistant phenotypes. This review highlights recent methodological and conceptual advances that have reshaped the understanding of platinum resistance in EOC. We summarize state-of-the-art experimental platforms ranging from two- and three-dimensional culture systems to lineage-tracing technologies, single-cell sequencing, and integrated multi-omic strategies. Together, these approaches enable dynamic mapping of clonal evolution and adaptive responses under therapeutic pressure. We also discuss emerging therapeutic strategies aimed at overcoming resistance, including inhibitors of DNA damage response, antibody–drug conjugates, anti-angiogenic agents, immunotherapies, and targeted drug delivery systems. Recent clinical advances illustrate the translational potential of mechanism-based interventions. Despite these promising developments, durable clinical responses remain limited, emphasizing the need for biomarker-guided combination therapies. An integrated, multi-omics–driven, and patient-tailored framework will be critical for re-sensitizing resistant tumors and improving long-term outcomes in ovarian cancer.