Transgelin 2 guards T cell lipid metabolism and anti-tumor function

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids. Fatty acid-binding protein 5 (FABP5) plays a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8+ T cells. Importantly, however, the mechanisms governing this immunometabolic axis remain unexplored. Here, we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration, and anti-cancer function in CD8+ T cells. We found that TAGLN2 interacts with FABP5, enabling its cell surface localization and function in 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, thereby 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. Profiling of single-cell transcriptome of total tumor-infiltrating CD45+CD3+ T cells sorted from Xbp1fl/fl or Xbp1fl/flCd4Cre mice bearing metastatic OvCa.