Medium chain fatty acid sensing receptor GPR84 limits antitumor immunity mediated by CD4 T cells in mice

CD4+ T cells play an important role in antitumor immunity due to their capacity to acquire highly functional effector states and cytotoxic-like programs in the tumor microenvironment. However, the mechanisms underlining this process remain largely undefined. Herein, we identify the medium chain fatty acid-sensing receptor GPR84 as a metabolic checkpoint that restricts the antitumor immunity mediated by CD4+ T cells. GPR84 upregulation was detected in tumor-infiltrating CD4+ T cells, and in the absence of GPR84, CD4+ T cells exhibited enhanced tumor control, associated with increase in their proliferation and survival, and with a reprogramming toward a more functionally competent state characterized by increased polyfunctional cytokine production and reduced expression of inhibitory receptors, without accumulation of regulatory T cells. In the tumor antigen-specific mouse model, GPR84 deficiency drastically improved the therapeutic efficacy of adoptively transferred CD4+ T cells. Mechanistically, without GPR84, CD4+ T cells, by upregulating mTORC1 signaling activity, metabolically enhance both glycolysis and mitochondrial activities, thereby gearing toward tumor-killing cytotoxic phenotypes. Importantly, pharmacologic inhibition of GPR84 drastically improves the effectiveness of both PD-1 blockade therapy and adoptive cell transfer. Together, these findings validate GPR84 as a key regulator of CD4+ T-cell metabolic fitness and establish the extracellular lipid sensing pathway as a targetable axis for improving the efficacy and responsiveness of cancer immunotherapies.