多发性骨髓瘤来源的二氧化硫通过诱导线粒体功能障碍驱动 CAR-T 细胞耗竭

Metabolic disorders mediated chimeric antigen receptor - T cell (CAR-T) exhaustion impaired cancer immunotherapy. Endogenous sulfur dioxide (SO 2 ) derived from L-cysteine catalysis regulated immune cell functions.

However, its role in CAR-T cell exhaustion remained unknown. In this study, we identified that SO 2 accumulated in the bone marrow microenvironment of relapsed multiple myeloma patients inhibited CD8 + T cell and CAR-T cell infiltration and promoted a transcriptional profile consistent with functional exhaustion, leading to impaired antitumor immunity. Tumor cell derived SO 2 altered mitochondrial morphology and disrupted mitochondrial membrane potential in CAR-T cells, accompanied by impaired cytokine secretion and loss of cytotoxic function.

Mechanistically, SO 2 enhanced interaction of dynamin-related protein 1 (DRP1) and voltage-dependent anion channel 1 and mitochondrial fission via DRP1 sulphenylation at cysteine 607 (Cys607), with abnormal increases in DRP1 GTPase activity, disrupting mitochondrial integrity. Site mutation of Cys607 in CAR-T cells abrogated DRP1 sulphenylation and restored mitochondrial structure and improves antitumor immunity.

These findings define a novel redox-mediated mechanism of mitochondrial dysfunction in CAR-T cells exhaustion and identify the SO 2 -DRP1 axis as a potential therapeutic target to overcome metabolic exhaustion in CAR-T cell therapy.