The amino acid glutamine is critical to cancer cell survival and efforts to inhibit its metabolism for therapy have been underway since the 1950s. Multiple studies have since revealed that glutamine inhibition not only kills cancer cells directly but also supports anti-tumor immunity. But the first inhibitor of glutamine metabolism, DON, proved too promiscuous in its targeting and thus too toxic for clinical use. Researchers led by Ludwig Chicago Co-director Jeffrey Rathmell employed an in vivo CRISPR screen on CD8+ T cells in the tumor microenvironment (TME) to identify a more specific inhibitor of glutamine metabolism for cancer therapy. They reported in an October publication in The Journal of Immunology that while other glutamine-metabolizing enzymes are essential to T cells, the deletion of glutamine synthetase (GS) uniquely improved CD8+ T cell fitness in the tumor microenvironment (TME), boosting mitochondrial respiration and resistance to reactive oxygen species, among other things. Both GS deletion and pharmacological inhibition improved tumor control in mouse models. GS-deficient CD8+ T cells transferred into mice were more resilient under the metabolic stress of the TME, better at killing cancer cells and expressed genes known to be markers of memory and stemness. Jeffrey and his colleagues argue that their findings suggest GS-inhibition might be a powerful therapeutic companion for multiple cancer immunotherapies.
Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment
The Journal of Immunology, 2025 October 31