Mitochondrial Carrier SLC25A13 Drives Ferroptosis Resistance and Immune Evasion via a STAT3-IFI6 Circuit in Breast Cancer

Triple-negative breast Cancer (TNBC) remains poorly responsive to immunotherapy, and how Ferroptosis can be leveraged to enhance antitumor immunity is unclear. Here, we identify the mitochondrial aspartate/glutamate carrier SLC25A13 as a key immunometabolic driver in TNBC. SLC25A13 is upregulated in breast Cancer, predicts poor prognosis, and is associated with reduced CD8⁺ T-cell infiltration. Functionally, SLC25A13 promotes tumor growth, migration, and metastasis while suppressing Ferroptosis and weakening CD8⁺ T-cell-mediated cytotoxicity. Mechanistically, SLC25A13 interacts with STAT3, enhances complex I-linked Oxidative Phosphorylation, restrains mitochondrial ROS, and promotes STAT3 activation and nuclear translocation. Nuclear STAT3 directly induces IFI6, which preserves mitochondrial function, limits lipid peroxidation and Fe^{2 +} accumulation, and thereby confers Ferroptosis resistance and immune evasion. Through structure-guided screening, we identified HY-QS02682823 as a small-molecule degrader of SLC25A13 that triggers lysosome-dependent SLC25A13 loss, enhances Ferroptosis, restores CD8⁺ T-cell effector function, and improves the efficacy of anti-PD-1 therapy in syngeneic TNBC models. These findings identify the SLC25A13-STAT3-IFI6 axis as a key regulator of Ferroptosis resistance and immune evasion in TNBC.