Dynamic regulation of lysine and arginine metabolism promotes immune evasion by limiting T cell function in cancer

Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment. It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism. We identified that up-regulation of solute carrier family 7 member 1 (SLC7A1) increased arginine utilization and promoted tumor growth, whereas down-regulation of SLC7A2 decreased lysine catabolism to support immune evasion. Repression of lysine catabolism in tumor cells reduced glutaconic acid (GC), a medium-chain acyl-CoA dehydrogenase–dependent lysine catabolite that has immunostimulatory effects on antitumor CD8 T cells. GC modified pyruvate kinase M2 (PKM2) through posttranslational glutaconylation at key lysine residues Lys 336 (K336) and K337. This modification reinforced PKM2 dimers, transcriptionally driving metabolic reprogramming and reinvigorating antitumor CD8 T cells. Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion.