Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion

TLDR

Tumor metabolic traits hinder immune cell function and limit cancer immunotherapy efficacy. The study aimed to dismantle the immunosuppressive tumor microenvironment by using a glutamine antagonist. This was achieved by metabolically targeting glutamine pathways to disrupt tumor cell metabolism. Glutamine blockade suppressed tumor oxidative and glycolytic metabolism, reducing hypoxia, acidosis, and nutrient depletion, while simultaneously enhancing effector T cells’ oxidative metabolism and long‑lived activation, thereby revealing a metabolic checkpoint that can be exploited for potent antitumor responses.

Abstract

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.