Activation of lipid synthesis following glycolysis is required for CD8+ T cells to acquire antitumor immune activity.

Activated CD8+ T cells undergo metabolic reprogramming and shift to aerobic glycolysis to fulfill their energy and biosynthetic demands. However, the downstream pathways linking glycolytic flux to potent antitumor immunity remain unclear. In this study, we used a T-cell-specific phosphoglycerate mutase 1 (Pgam1)-deficient mouse model to demonstrate that accelerated lipid synthesis induced by glycolysis is necessary for CD8+ T cells to acquire antitumor activity. Pgam1 deficiency severely impaired antitumor activity and intratumoral infiltration in the MC38-OVA tumor model. Transcriptomic profiling of Pgam1-deficient CD8+ T cells activated in vitro revealed that Pgam1 deficiency caused a marked reduction in the lipid biosynthetic program and altered lipid composition. We found that in Pgam1-deficient CD8+ T cells, TCR stimulation dose not induce the upregulation of the Srebf1 and Srebf2 genes, which encode the master transcription factors Srebp1 and Srebp2, respectively, that regulate lipid synthesis. Pharmacological inhibition of SREBPs by fatostatin attenuated effector functions, such as TCR-induced proliferation, cytokine production, and cytotoxicity. These findings indicate that the activation of SREBP-dependent lipid synthesis pathways, which follow glycolysis, is important for the acquisition of antitumor activity by CD8+ T cells.