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

Abstract

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 (T_eff) and memory (T_m) 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 <i>Tkt</i> or <i>Taldo1</i> impaired NADPH production, leading to ribose-5-phosphate (R5P) accumulation, oxidative stress, reduced lipid synthesis, mitochondrial dysfunction, and compromised T_eff cell proliferation, cytokine production, and antitumor efficacy. Conversely, enhancing non-oxPPP activity promoted T_m 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.