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

ABSTRACT: 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 functi

SUBMITTER: Yu Z 

PROVIDER: S-EPMC12859796 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature