Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8):
e2526325123
Jingyu Feng,
Qian Zhang,
Li Luo,
Zhichao Gu,
Wen Liu,
Jingsong Xu,
Mengxin Qi,
Zhongji Meng,
Lin Li,
Liangliang Lin,
Zhuoshun Yang,
Huafeng Zhang.
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.
Keywords: CD8+ T cell; NADPH; memory T cell; nonoxidative pentose phosphate pathway