ABSTRACT 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.
Zhu et al. (Mon,) studied this question.