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 () 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 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-GRM4 and CD8-GRM4 correlated with improved survival in patients with melanoma. Targeting GRM4 represents a new approach for cancer immunotherapy.