Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

In this study, we report a novel role of metabotropic glutamate receptor 4 (GRM4) in suppressing antitumor 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. Mechanistically, perturbation of GRM4 resulted in a strong antitumor immunity by promoting natural killer (NK), CD4⁺, and CD8⁺ T cells toward an activated, proliferative, and functional phenotype. Single-cell RNA sequencing and T cell receptor profiling further defined the clonal expansion and immune landscape changes in CD8⁺ T cells. We further showed that Grm4^−/− intrinsically activated interferon-γ production in CD8⁺ T cells through cyclic adenosine 3′,5′-monophosphate (cAMP)/cAMP response element binding protein–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 patients with melanoma. Targeting GRM4 represents a new approach for cancer immunotherapy.