2025年6月3日，上海交通大学医学院邹强研究小组在《自然—细胞生物学》杂志发表论文，报道了乳酸脱氢酶B促进肿瘤浸润性CD8⁺ T细胞的双下垂和衰竭。

在这里，研究组证明乳酸脱氢酶B （LDHB）促进细胞内CD8⁺ T细胞的双胞下垂和衰竭，导致抗肿瘤免疫受损。SLC7A11介导的胱氨酸摄取被CD8⁺ T细胞诱导二硫垂，这在衰竭的CD8⁺ T细胞的发育中起关键作用。在衰竭的CD8⁺ T细胞中，LDHB通过与G6PD相互作用来限制葡萄糖-6-磷酸脱氢酶（G6PD）的活性，引导NADPH耗竭，从而引发二硫垂。因此，T细胞中LDHB的缺失阻止了二硫塌陷依赖性CD8⁺ T细胞的衰竭，提高了抗肿瘤免疫能力。在机制上，STAT3引导LDHB表达限制G6PD活性并介导衰竭的CD8⁺ T细胞的二亢。他们的研究结果强调了二硫下垂和铁下垂在驱动CD8⁺ T细胞衰竭中的独特作用，并提出了一种针对LDHB的潜在治疗策略。

据悉，细胞内二硫化物的异常积累促进癌细胞二硫下垂；然而，二硫胁迫如何影响肿瘤浸润性CD8⁺ T细胞功能仍不清楚。

附：英文原文

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

Author: 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

Issue&Volume: 2025-06-03

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.

DOI: 10.1038/s41556-025-01673-2

Source: https://www.nature.com/articles/s41556-025-01673-2