Targeting CAR-T cell senescence through Mysm1-SSBP1 axis improves persistence and therapeutic efficacy

Chimeric antigen receptor (CAR)-T cell immunotherapy has demonstrated remarkable success in treating hematological malignancies, yet its clinical efficacy remains limited, particularly against solid tumors. Emerging evidence implicates T cell senescence as a key immunosuppressive barrier in cancer immunotherapy. In this study, we engineered Mysm1-overexpressing CAR-T cells and identified Mysm1 augmentation significantly enhances cytotoxic function and anti-tumor activity across multiple preclinical models. Integrated transcriptomic and biochemical analyses revealed that Mysm1 sustains mitochondrial homeostasis in CAR-T cells by interacting with SSBP1. Mechanistically, MYSM1 catalyzed K48-linked deubiquitination of SSBP1, thereby preserving mitochondrial function and mitigating CAR-T cell senescence. This intervention resulted in prolonged persistence and sustained anti-tumor efficacy in both murine and human CAR-T cells. Our findings unveil a novel strategy to counteract CAR-T cell senescence and establish Mysm1 as a promising therapeutic target for enhancing CAR-T cell immunotherapy.