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Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy

Reprogramming lipid metabolism reverses effector T cell senescence and enhances antitumor immunity in mouse models. Stopping senescence Promoting functional T cell responses is essential for cancer immunotherapies to be effective. However, there are several strategies by which tumor cells and immune cells within the tumor microenvironment can disrupt T cell functionality. Here, Liu et al. found that tumor cells and regulatory T cells induce senescence of conventional T cells, limiting their ability to kill tumor cells. The authors showed that this was mediated by dysregulation of lipid metabolism by conventional T cells, which could be reversed with pharmacological interventions. Normalizing lipid metabolism and reversing senescence resulted in better control of tumor burden and extended survival in mouse models of melanoma and breast cancer. Thus, targeting lipid metabolism may further improve cancer immunotherapies. The functional state of T cells is a key determinant for effective antitumor immunity and immunotherapy. Cellular metabolism, including lipid metabolism, controls T cell differentiation, survival, and effector functions. Here, we report that development of T cell senescence driven by both malignant tumor cells and regulatory T cells is a general feature in cancers. Senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism. This unbalanced lipid metabolism results in changes of expression of lipid metabolic enzymes, which, in turn, alters lipid species and accumulation of lipid droplets in T cells. Tumor cells and Treg cells drove elevated expression of group IVA phospholipase A2, which, in turn, was responsible for the altered lipid metabolism and senescence induction observed in T cells. Mitogen-activated protein kinase signaling and signal transducer and activator of transcription signaling coordinately control lipid metabolism and group IVA phospholipase A2 activity in responder T cells during T cell senescence. Inhibition of group IVA phospholipase A2 reprogrammed effector T cell lipid metabolism, prevented T cell senescence in vitro, and enhanced antitumor immunity and immunotherapy efficacy in mouse models of melanoma and breast cancer in vivo. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and provide a new target for tumor immunotherapy.