Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids ^1-3 . During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8 ⁺ T cells ^4,5 . Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8 ⁺ T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8 ⁺ T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8 ⁺ T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8 ⁺ T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.
Competing Interests: COMPETING INTERESTS / DISCLOSURES J.R.C.-R. holds patents on the use immune modulators for OvCa treatment and serves as scientific consultant for Moderna, Immagene B.V., and Autoimmunity Biologic Solutions, Inc. D.Z. reports institutional grants from Merck, Genentech, AstraZeneca, Plexxikon, and Synthekine, and personal fees from AstraZeneca, Xencor, Memgen, Takeda, Synthekine, Immunos, Tessa Therapeutics, Miltenyi, and Calidi Biotherapeutics. D.Z. owns a patent on use of oncolytic Newcastle Disease Virus for cancer therapy. J.R.C.-G. has stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; receives licensing fees from Anixa Biosciences for the patent of FSHCER T cells; receives honorarium from Alloy Therapeutics; and intellectual property with Compass Therapeutics and Anixa Biosciences; and is co-founder of Cellepus Therapeutics, a company that develops allogeneic gamma/delta CAR T cells. All other authors declare no potential conflicts of interest.