2. Academic Validation
  3. Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells

Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8+ T cells

  • Nat Cell Biol. 2025 Jun;27(6):972-982. doi: 10.1038/s41556-025-01673-2.
Jie Wan # 1,  Jian-Hong Shi # 2,  Min Shi # 3,  Haiyan Huang # 4,  Zhen Zhang 5,  Wenyan Li 6,  Chenyue Guo 1,  Rujuan Bao 1,  Xiaoyan Yu 1,  Qiaoqiao Han 1,  Xian Du 1,  Song Li 1,  Youqiong Ye 1,  Xingang Cui 7,  Xia Li 8,  Jing-Hua Li 9,  Qiang Zou 10
Affiliations

Affiliations

  • 1 Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Central Laboratory, Hebei International Joint Research Center for Digital Twin Diagnosis and Treatment of Digestive Tract Tumors, Affiliated Hospital of Hebei University, Baoding, China.
  • 3 Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.
  • 6 Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. cuixingang@xinhuamed.com.cn.
  • 8 Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China. 60230033@sdutcm.edu.cn.
  • 9 Department of Hepatobiliary Surgery, Baoding Key Laboratory of Precision Diagnosis and Treatment of Digestive Tract Tumors, Affiliated Hospital of Hebei University, Baoding, China. lijinghua@hbu.edu.cn.
  • 10 Hongqiao International Institute of Medicine, Tongren Hospital & Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Qzou1984@sjtu.edu.cn.
  • # Contributed equally.
PMID: 40461882 DOI: 10.1038/s41556-025-01673-2
Abstract

The aberrant accumulation of intracellular disulfides promotes Cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that Lactate Dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell Disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces Disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering Disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate Disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of Disulfidptosis and Ferroptosis in driving CD8+ T cell exhaustion and suggest a potential therapeutic strategy to target LDHB in Cancer Immunotherapy.

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