Work

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

Year: 2026

Type: article

Abstract: 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 underlying CAR-T cell exhaustion remained unknown. In this study, we identified SO 2 accumulated in the bone marrow microenvironment of relapsed multiple myeloma patients inhibited CD8 + and CAR-T cell infiltration and a transcriptional profile consistent with functional exhaustion, leading to impaired antitumour 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 dynamin-related protein 1 (DRP1) - voltage-dependent anion channel 1 interaction and mitochondrial fission via DRP1 sulphenylation at cysteine 607, with abnormal increases in DRP1 GTPase activity, disrupting mitochondrial integrity. Site mutation of cysteine 607 in CAR-T cells abrogated DRP1 sulphenylation and restored mitochondrial structure and improves antitumour 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. Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction: MM derived-SO 2 mediated DRP1 sulphenylation at C607 sustained its location in mitochondrial membrane and promoted its interaction with VDAC1, triggering excessive mitochondria fission, ATP loss, cytokines and cytotoxicity reduction and impairing CAR-T anti-tumor immunity. • Multiple myeloma-derived sulfur dioxide impairs anti-tumor immunity of CAR-T cell; • SO 2 sulphenylates DRP1 at Cys607 to promote excessive mitochondrial fission and reduce cytokine production and cytotoxicity of CAR-T cell; • Site mutation of DRP1 at Cys607 abolishes DRP1 sulphenylation and preserves mitochondrial integrity; • Targeting the SO 2 –DRP1 axis may enhance durability of CAR-T cell therapy.

Source: Redox Biology

DOI: 10.1016/j.redox.2026.104040