The metabolic characteristics of tumors present considerable hurdles to immune cell function and cancer immunotherapy. Using a glutamine antagonist, we metabolically dismantled the immunosuppressive microenvironment of tumors. We demonstrate that glutamine blockade in tumor-bearing mice suppresses oxidative and glycolytic metabolism of cancer cells, leading to decreased hypoxia, acidosis, and nutrient depletion. By contrast, effector T cells responded to glutamine antagonism by markedly up-regulating oxidative metabolism and adopting a long-lived, highly activated phenotype. These divergent changes in cellular metabolism and programming form the basis for potent antitumor responses. Glutamine antagonism therefore exposes a previously undefined difference in metabolic plasticity between cancer cells and effector T cells that can be exploited as a “metabolic checkpoint” for tumor immunotherapy.

Immune cell activation and differentiation occurs concurrently with metabolic reprogramming. This insures that activated cells generate the energy and substrates necessary to perform their specified function. Likewise, the metabolic programs amongst different cells of the immune system vary. By targeting different metabolic pathways, these differences allow for selective regulation of immune responses. Further, the relative susceptibility of cells to a metabolic inhibitor is dictated by their metabolic demands; cellular selectivity is based on demand. Therefore where differences exist in metabolic pathways between healthy and pathogenic cells, there is opportunity for selective regulation with agents lacking intrinsic specificity. There are now a host of studies demonstrating how inhibitors of metabolism (for example glycolysis, glutamine metabolism, and fatty acid oxidation) can regulate immune responses and treat immune mediated pathogenesis. In this brief review we detail how inhibitors of metabolism can be employed to regulate immune responses in both autoimmunity and transplantation.