ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR269/055/SRR26943555/SRR26943555.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR269/057/SRR26943557/SRR26943557.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR269/054/SRR26943554/SRR26943554.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR269/056/SRR26943556/SRR26943556.fastq.gzprimary200OKGenomicsWeill Cornell Medicinehttps://www.ebi.ac.uk/ena/browser/view/PRJNA1044826Mus musculusxref:PubMed:39443795Mounting 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. Overall design: Profiling of single-cell transcriptome of total tumor-infiltrating CD45+CD3+ T cells sorted from Xbp1fl/fl or Xbp1fl/flCd4Cre mice bearing metastatic OvCa.ENAfalseTransgelin 2 guards T cell lipid metabolism and anti-tumor functionTransgelin 2 guards T cell lipid metabolism and anti-tumor function2025-09-242025-01-03PRJNA1044826GSE2485951009039443795