Wan Jie, Shi Jian-Hong, Shi Min, Huang Haiyan, Zhang Zhen, Li Wenyan, Guo Chenyue, Bao Rujuan, Yu Xiaoyan, Han Qiaoqiao, Du Xian, Li Song, Ye Youqiong, Cui Xingang, Li Xia, Li Jing-Hua, Zou Qiang
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.
Central Laboratory, Hebei International Joint Research Center for Digital Twin Diagnosis and Treatment of Digestive Tract Tumors, Affiliated Hospital of Hebei University, Baoding, China.
Nat Cell Biol. 2025 Jun 3. doi: 10.1038/s41556-025-01673-2.
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.
细胞内二硫键的异常积累会促进癌细胞的二硫键程序性坏死；然而，二硫键应激如何影响肿瘤浸润性CD8 T细胞的功能仍不清楚。在此，我们证明乳酸脱氢酶B（LDHB）促进肿瘤内CD8 T细胞的二硫键程序性坏死和耗竭，导致抗肿瘤免疫受损。SLC7A11介导的CD8 T细胞摄取胱氨酸会诱导二硫键程序性坏死，这在耗竭的CD8 T细胞的发育中起关键作用。LDHB通过与葡萄糖-6-磷酸脱氢酶（G6PD）相互作用，限制耗竭的CD8 T细胞中的G6PD活性，导致NADPH耗竭，从而引发二硫键程序性坏死。因此，T细胞中LDHB的缺失可防止二硫键程序性坏死依赖性的CD8 T细胞耗竭，并增强抗肿瘤免疫。从机制上讲，STAT3指导LDHB的表达，以限制G6PD活性并介导耗竭的CD8 T细胞中的二硫键程序性坏死。我们的结果突出了二硫键程序性坏死和铁死亡在驱动CD8 T细胞耗竭中的不同作用，并提出了一种在癌症免疫治疗中靶向LDHB的潜在治疗策略。
