Immune-checkpoint inhibitors and adoptive tumor-infiltrating lymphocyte (TIL) therapies have profoundly improved the survival of patients with melanoma. However, most patients don’t react to these agents, and lots of responders experience disease relapse. Although numerous innovative remedies are being explored to counterbalance the limitations of those agents, novel therapeutic combinations with immunotherapies have the possibility to enhance patient responses. Within this study, we evaluated the antimelanoma activity of immunotherapy combinations with Telaglenastat (CB-839), a powerful glutaminase inhibitor (GLSi) which has favorable systemic tolerance. In in vitro TIL:tumor coculture studies, CB-839 treatment improved the cytotoxic activity of autologous TILs on patient-derived melanoma cells. CB-839 treatment decreased the conversion of glutamine to alpha-ketoglutarate (αKGA) more potently in tumor cells versus TILs during these cocultures. These results claim that CB-839 may improve immune function inside a tumor microenvironment by differentially altering tumor and immune cell metabolic process. In vivo CB-839 treatment activated melanoma antigen-specific T cells and improved their tumor killing activity within an immune-competent mouse type of adoptive T-cell therapy. Furthermore, the mixture of CB-839 with anti-PD1 or anti-CTLA4 antibodies elevated tumor infiltration by effector T cells and improved the antitumor activity of those checkpoint inhibitors inside a high mutation burden mouse melanoma model. Responsiveness to those treatments seemed to be supported by a rise of interferon gamma (IFNγ)-connected gene expression within the tumors. Together, these results give a strong rationale for mixing CB-839 with immune therapies to enhance effectiveness of those treatments against melanoma.