Abstract IA015: Enhancing T cell metabolic fitness for ovarian cancer immunotherapy

Abstract Ovarian cancer imposes profound metabolic and functional barriers on tumor-infiltrating T cells, limiting their therapeutic potential. We identified the cytoskeletal organizer transgelin-2 (TAGLN2) as a critical regulator of lipid metabolism that enables protective CD8+ T cell function in this malignancy. TAGLN2 interacted with fatty-acid-binding protein 5 (FABP5) to promote its cell-surface localization, facilitating efficient fatty acid uptake, robust mitochondrial respiration, and optimal cytotoxic activity. In patient tumors, the ovarian cancer microenvironment triggered endoplasmic reticulum (ER) stress responses that repressed TAGLN2 in infiltrating CD8+ T cells, driving a metabolically impaired, dysfunctional state. Restoring TAGLN2 expression in ER-stressed T cells enhanced lipid utilization, mitochondrial function, and antitumor activity. Importantly, chimeric antigen receptor (CAR) T cells engineered to overexpress TAGLN2 resisted tumor-induced ER stress and demonstrated therapeutic efficacy in preclinical models of metastatic ovarian cancer. These findings define TAGLN2 as a pivotal cytoskeletal determinant of T cell lipid metabolism in the ovarian cancer microenvironment and highlighted the potential of preserving the TAGLN2–FABP5 axis to overcome metabolic suppression and improve cellular immunotherapy in these tumors. Citation Format: Juan R. Cubillos-Ruiz. Enhancing T cell metabolic fitness for ovarian cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr IA015.