<p>Standard treatment for advanced ovarian cancer involves initial surgery followed by platinum-based chemotherapy. Although most patients are sensitive, most relapses occur at a later stage, highlighting the urgent need to understand the tumour microenvironment following neoadjuvant chemotherapy (NACT). To explore the mechanisms underlying chemotherapy resistance, we analysed published single-cell RNA sequencing (scRNA-seq) data from patients with high-grade serous ovarian cancer and performed several in vitro and in vivo experiments to investigate the role of prostaglandins in immunosuppressive microenvironment formation. Prostaglandin-mediated immunosuppressive microenvironment formation was a critical contributor to chemotherapy resistance following cisplatin treatment. Mechanistically, cisplatin-treated ovarian cancer cells induced the formation of myeloid-derived suppressor cells (MDSCs), which inhibited the cytotoxicity of CD8⁺T cells. Combination therapy with cisplatin and a prostaglandin-specific inhibitor restored CD8⁺T cell function and significantly improved the therapeutic efficacy compared with cisplatin monotherapy. Targeting prostaglandins may be a promising therapeutic strategy for overcoming chemotherapy resistance in ovarian cancer.</p>