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 Fe2 + 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.
© 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH.