The complex mechanism regulating the immunosuppressive tumor microenvironment (TME) remains poorly understood. Here, we reported a novel role of the metabotropic glutamate receptor-4 (GRM4) in suppressing the anti-tumor immunity. We revealed in three murine syngeneic tumor models (B16, MC38, and 3LL) that either genetic knockout (Grm4^−/−) or pharmacological inhibition led to significant delay in tumor growth and synergized with immune checkpoint inhibitors in male mice. Mechanistically, perturbation of GRM4 resulted in a strong anti-tumor immunity by promoting nature killer (NK), CD4⁺ and CD8⁺ T cells towards an activated, proliferative, and functional phenotype. Single-cell RNA-sequencing and T Cell Receptor (TCR) profiling further defined the clonal expansion and immune landscape changes in CD8⁺ T cells. Mechanistically, Grm4^-/- intrinsically activated IFN-g production in CD8⁺ T cells through cAMP/CREB-mediated pathway. Our study appears to be of clinical significance as a signature of NK^high-GRM4^low and CD8^high-GRM4^low correlated with improved survival in melanoma patients. Therefore, targeting GRM4 could be exploited as a new approach for cancer immunotherapy. 

KO refers to Grm4^-/- Mice