Preclinical study reveals that glycolysis-driven lipid synthesis is required for CD8+ T-cell antitumor function in mice, indicating SREBP activation as a key immunometabolic driver.
Key Points
To determine how downstream metabolic pathways linking glycolytic flux to lipid synthesis regulate the antitumor immune activity of CD8+ T cells.
Generated T-cell-specific phosphoglycerate mutase 1 (Pgam1)-deficient mice and evaluated tumor growth and T-cell infiltration using the MC38-OVA tumor model.
Conducted transcriptomic profiling and lipid composition analysis on in vitro-activated Pgam1-deficient CD8+ T cells.
Evaluated CD8+ T-cell proliferation, cytokine production, and cytotoxicity following pharmacological inhibition of SREBPs using fatostatin.
Pgam1 deficiency severely impaired CD8+ T-cell antitumor activity and intratumoral infiltration in the MC38-OVA model.
TCR stimulation failed to upregulate Srebf1 and Srebf2 in Pgam1-deficient CD8+ T cells, resulting in a marked downregulation of the lipid biosynthetic program and altered lipid composition.
Pharmacological blockade of SREBPs with fatostatin attenuated TCR-induced proliferation, cytokine production, and cytotoxic effector functions.