Folate receptor-α targeted therapies in ovarian cancer: recent advances and emerging therapeutic strategies

Epithelial ovarian cancer (EOC) remains a biologically heterogeneous and therapeutically difficult malignancy because most advanced-stage tumors initially respond to platinum-taxane chemotherapy but later recur with progressively reduced platinum sensitivity. Folate receptor-alpha (FRα/FOLR1) has become a clinically relevant precision-oncology target because it is enriched in high-grade serous ovarian carcinoma, is relatively shielded from circulating drugs in many polarized normal epithelia, and undergoes receptor-mediated internalization after ligand or antibody binding. This review critically evaluates FRα not merely as a folate transporter but as a biomarker, delivery portal, immune target and resistance-associated therapeutic axis. The revised manuscript expands the quantitative clinical discussion, including the magnitude and limits of benefit from PARP inhibitor maintenance, anti-angiogenic strategies, immune-checkpoint blockade and FRα-directed antibody-drug conjugates. Mirvetuximab soravtansine is positioned as the current clinical benchmark because it has demonstrated superiority over chemotherapy in FRα-positive platinum-resistant ovarian cancer, while earlier naked antibodies, folate-drug conjugates, peptide vaccines and first-generation CAR-T cells have shown biological feasibility without consistently durable survival benefit. The expanded discussion integrates antigen density, epithelial polarity, endocytosis/recycling, bystander payload release, ocular toxicity, P-glycoprotein efflux, tubulin-payload resistance, tumor-associated macrophages, regulatory T cells, HLA restriction, biomarker variability and lesion-level target heterogeneity. Emerging strategies such as eribulin-based ADCs, IgE antibodies, FRα-targeted photodynamic therapy, PET/SPECT imaging, folate nanoparticles, radioligands and rational combinations are discussed as mechanism-led extensions rather than generic additions. Overall, FRα-targeted therapy in ovarian cancer is best understood as a biomarker-adapted platform that requires standardized testing, quantitative pharmacology, toxicity mitigation and resistance-aware trial design.