Novel approaches to modulate CAR-T cell function by targeting the tumor microenvironment in ovarian cancer

Ovarian cancer (OC) remains one of the most lethal gynecological malignancies despite advances in conventional therapeutic approaches. The dismal approximately 30% five-year survival rate for advanced disease highlight the urgent need for innovative treatment strategies. Chimeric antigen receptor T (CAR-T) cell therapy, having revolutionized treatment paradigms in hematological malignancies, faces significant challenges when applied to the complex immunosuppressive tumor microenvironment (TME) of ovarian cancer. This comprehensive review investigates critical research questions regarding the extent to which cellular and molecular components of the ovarian cancer TME inhibit CAR-T cell cytotoxic function, and the signaling patterns associated with reduced CAR-T cell infiltration or persistence in tumor masses. We systematically examine the multifaceted immunosuppressive mechanisms within the ovarian cancer TME and evaluate breakthrough strategies designed to overcome these barriers, including next-generation CAR engineering, combinatorial therapeutic approaches, and innovative TME-modulating technologies. The insights presented here provide a crucial roadmap for translating CAR-T therapy from promising concept to clinical reality in ovarian cancer treatment, potentially transforming outcomes for patients with this recalcitrant malignancy where innovative therapeutic options are urgently needed. Novel CAR-T strategies enhance efficacy in the immunosuppressive ovarian TME. Hypoxia and metabolic stress limit CAR-T cell persistence and cytotoxic function. Armored CAR-T cells resist TGF-β signaling and improve intratumoral activity. CRISPR editing enables checkpoint-resistant and durable CAR-T cell responses. Nanoparticles deliver modulators that reprogram TME to support CAR-T therapy. Engineered probiotics modulate immune tone and support CAR-T infiltration. Metabolic conditioning enhances CAR-T function in nutrient-deprived tumors. Multi-antigen CAR-Ts reduce escape and increase targeting precision in EOC. Translational hurdles include scalability, regulatory gaps, and treatment costs. Integrative, personalized TME-targeting may unlock CAR-T potential in EOC.