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

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.