Nonoxidative pentose phosphate pathway regulates CD8 <sup>+</sup> 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 Tkt or Taldo1 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Jingyu Feng
Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology
Qian Zhang
Li Luo
Department of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University
Zhichao Gu
Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Wen Liu
Jingsong Xu
Science and Technology on Surface Physics and Chemistry Laboratory
Mengxin Qi
Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology
Zhongji Meng
Department of Infectious Diseases, Regulatory Mechanism and Targeted Therapy for Liver Cancer Shiyan Key Laboratory, Hubei Provincial Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Institute of Biomedical Research, Hubei University of Medicine
Lin Li
Liangliang Lin
Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology
Zhuoshun Yang
Department of Infectious Diseases, Regulatory Mechanism and Targeted Therapy for Liver Cancer Shiyan Key Laboratory, Hubei Provincial Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Institute of Biomedical Research, Hubei University of Medicine
Huafeng Zhang
State Key Laboratory of Immune Response and Immunotherapy, Department of Rheumatology and Immunology, The First Affiliated Hospital of University of Science and Technology of China, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China