Advances in Next-Generation Immunotherapies for Ovarian Cancer: Mechanisms of Immune Evasion and Novel Therapeutic Targets.

Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its clinical benefit for OC has been limited, in part due to an extremely immunosuppressive tumor microenvironment (TME) and diverse, overlapping immune evasion mechanisms. In this review, we present a comprehensive and timely synthesis of next-generation immunotherapeutic approaches for ovarian cancer, emphasizing strategies that overcome the immunosuppressive tumor microenvironment and improve clinical responsiveness. We describe the emerging molecular mechanisms of immune evasion in OC, including altered antigen presentation, inhibition of T-cell activation (e.g., via immunological checkpoints, metabolic reprogramming), polarization of tumor-associated macrophages (TAMs), and dysfunction of natural killer (NK) cells. We also critically examine several emerging therapeutic approaches, including combination immune checkpoint blockade (ICB), bispecific T-cell engagers (BiTEs), neoantigen-based vaccines, chimeric antigen receptor (CAR)-T- and CAR-NK-cell therapies, oncolytic viruses (OVs), and nanoparticle-mediated immunomodulation. In addition, we highlight recent advances in tumor microenvironment-targeted therapies for ovarian cancer, focusing on strategies that modulate non-lymphoid components such as cancer-associated fibroblasts (CAFs), hypoxia-driven signaling, and the PI3K/AKT/mTOR axis to enhance antitumor immune responsiveness. Finally, we discuss how predictive biomarkers, multi-omics systems, and patient-derived organoid models are accelerating the development and deployment of precision immunotherapies for OC. We would like to highlight the translational promise of next-generation immunotherapies and identify novel molecular targets that may be leveraged to achieve durable responses in OC.