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.

细胞内二硫化物的异常积累促进癌细胞二硫下垂;然而，二硫键应激如何影响肿瘤浸润的 CD8⁺ T 细胞功能仍然未知。在这里，我们证明乳酸脱氢酶 B （LDHB） 促进肿瘤内 CD8⁺ T 细胞二硫线垂和耗竭，导致抗肿瘤免疫受损。CD8⁺ T 细胞对 SLC7A11 介导的胱氨酸摄取诱导双硫下垂，这在耗竭的 CD8⁺ T 细胞的发育中起关键作用。LDHB 通过与 G6PD 相互作用来限制耗竭的 CD8⁺ T 细胞中的葡萄糖-6-磷酸脱氢酶 （G6PD） 活性，导致 NADPH 耗竭，从而触发二硫下垂。因此，T 细胞中 LDHB 的缺失可防止二硫线依赖性 CD8 ⁺ T 细胞耗竭并提高抗肿瘤免疫力。从机制上讲，STAT3 指导 LDHB 表达以限制 G6PD 活性并介导耗竭的 CD8⁺ T 细胞中的二硫线下垂。我们的结果强调了二硫线下垂和铁死亡在驱动 CD8⁺ T 细胞耗竭中的不同作用，并提出了在癌症免疫治疗中靶向 LDHB 的潜在治疗策略。