The Therapeutic Potential of iNKT Cells in the Treatment of Ovarian Cancer

Ovarian cancer (OC) remains the most lethal gynecological malignancy, and it is characterized by high heterogeneity, early metastatic dissemination, and frequent recurrence within 12–18 months after primary therapy. Despite progress in clinical management and drug development, the mortality rate remains high, and the biological drivers of OC aggressiveness are not fully understood. A major contributor to therapeutic resistance and disease progression is the ovarian tumor microenvironment (TME), which supports tumor growth and immune evasion. Its complexity poses significant challenges to the development of effective therapies. Current treatments, especially in advanced or recurrent stages, have limited efficacy. While immune checkpoint inhibitors (ICIs), such as anti-programmed death receptor (PD-1) and anti-programmed death ligand-1 (PD-L1) monoclonal antibodies, have revolutionized the treatment landscape of several solid tumors, their effectiveness in OC remains modest due to the non-inflamed, immunosuppressive nature of the disease. This highlights the need for alternative, more robust immunotherapeutic strategies. Invariant natural killer T (iNKT) cells engineered with chimeric antigen receptors (CARs) or T cell receptors (TCRs) are emerging as powerful candidates for next-generation adoptive cell therapies. This study aims to evaluate the therapeutic potential of iNKT cells in OC and to discuss their capacity to overcome immune resistance within the TME as a promising approach for next-generation immunotherapy. These dual-specific effector cells combine innate and adaptive properties, offering advantages such as human leukocyte antigen (HLA)-independent tumor recognition, natural tumor site homing, and the ability to modulate immunosuppressive TME. Preclinical studies have demonstrated their potential to overcome immune resistance and enhance antitumor responses in solid tumors, including OC. Altogether, iNKT-based therapies represent a promising and versatile platform to address the urgent need for more effective treatments for ovarian cancer.