Nonoxidative pentose phosphate pathway regulates CD8+ T cell immunity by maintaining NADPH homeostasis.

NADPH is essential for cellular biosynthesis and redox balance in CD8+ T cells. Here, we demonstrate that the nonoxidative pentose phosphate pathway (non-oxPPP), mediated by transketolase (TKT) and transaldolase (TALDO1), is critical for CD8+ T cell activation, proliferation, and memory formation by maintaining NADPH homeostasis. Metabolomic profiling and isotopic tracing revealed upregulated non-oxPPP flux in effector (Teff) and memory (Tm) CD8+ T cells, enabling a pentose cycle that amplifies NADPH yield and sustains metabolic fitness for T cell immunity. Genetic knockdown or pharmacological inhibition of Tkt or Taldo1 impaired NADPH production, leading to ribose-5-phosphate (R5P) accumulation, oxidative stress, reduced lipid synthesis, mitochondrial dysfunction, and compromised Teff cell proliferation, cytokine production, and antitumor efficacy. Conversely, enhancing non-oxPPP activity promoted Tm differentiation, persistence, and recall responses. Targeting the non-oxPPP represents a promising strategy to enhance cancer immunotherapy and vaccine efficacy by bolstering T cell effector and memory responses.