Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction

Metabolic disorders mediated chimeric antigen receptor - T cell (CAR-T) exhaustion impaired cancer immunotherapy. Endogenous sulfur dioxide (SO₂) 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 SO₂ 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 SO₂ altered mitochondrial morphology and disrupted mitochondrial membrane potential in CAR-T cells, accompanied by impaired cytokine secretion and loss of cytotoxic function. Mechanistically, SO₂ 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 SO₂-DRP1 axis as a potential therapeutic target to overcome metabolic exhaustion in CAR-T cell therapy.