Metabolic reprogramming via targeting the medium-chain fatty acid receptor enhances the anti-tumor activity of lymphocytes in cancer immunotherapy

Abstract The tumor microenvironment (TME) poses a significant challenge to the success of T cell-based immunotherapies. Upon arrival, following adoptive transfer, T cells encounter a harsh environment that is nutrient-deprived, acidic, hypoxic, and immunosuppressive, conditions that can impair their survival, proliferation, and ability to mount an effective antitumor response. The capacity of T cells to adapt to these adverse conditions is critical for determining their therapeutic efficacy and, ultimately, their ability to eliminate tumors. In this study, we investigate the role of the medium-chain fatty acid (MCFA) sensing receptor GPR84 in regulating T cell adaptation to the TME. We found that genetic deletion of GPR84 enhances this adaptation by boosting mitochondrial metabolism and increasing the capacity to acquire mitochondria from cancer cells. Additionally, in the absence of GPR84, T cells demonstrated robust expansion, increased production of cytokines, and reduced signs of exhaustion after adoptive transfer. As a result, GPR84-deficient T cells exhibited superior antitumor responses across multiple cancer models in-vivo. Together, our findings provide compelling evidence that targeting GPR84 represents a novel metabolic strategy to enhance T cell function and improve cancer immunotherapy.