Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control

Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using stable isotope tracing, we show that CD8+ effector T (Teff) cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a common precursor for glycogen, glycan, and GSL biosynthesis. Blocking GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2) or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8+ T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose - beyond energy production - that is required for CD8+ T cell responses in vivo.