Targeting MMGT1 enhances immunotherapy efficacy in triple-negative breast cancer.

The role of senescent tumor cells in modulating the immune microenvironment and influencing immunotherapy efficacy remains poorly understood. In this study, we investigate the function of the senescence-associated gene membrane magnesium transporter 1 (MMGT1) in triple-negative breast cancer (TNBC) immunotherapy. MMGT1 is upregulated in TNBC and correlates with poor prognosis. Mammary gland-specific knockout of Mmgt1 significantly impedes tumor growth. Mechanistically, MMGT1 promotes lipid metabolism by facilitating translocation of the SCAP-SREBP1 complex to the Golgi apparatus, thereby suppressing cellular senescence. Notably, senescent TNBC cells enhance CD8+ T cell proliferation and cytotoxicity through CCL20 secretion. Furthermore, a positive feedback loop exists between MMGT1 and SREBP1. In vivo, AZ191 downregulates MMGT1 expression, which suppresses tumor growth and enhances the efficacy of anti-PD-1 therapy. Collectively, these findings reveal a critical role for MMGT1 in shaping the TNBC immune microenvironment and suggest that targeting MMGT1 represents a promising strategy to improve anti-PD-1 immunotherapy outcomes.