Ultrasound‐Activated Nanoinhibitors Blocking the Chemo‐Immune Checkpoint to Overcome Chemotherapy‐Induced Immune Resistance

ABSTRACT Breast cancer features an immunosuppressive tumor microenvironment following chemotherapy and develops resistance to conventional immune checkpoint inhibitors. Through single‐cell database mining and in vitro analysis, we demonstrate that chemotherapy upregulates Xkr8 expression and promotes phosphatidylserine (PS) externalization, which mediates macrophage‐ and dendritic cell (DC)‐intrinsic immunosuppression. To address this, we fabricate an ultrasound‐activated nanoinhibitor (Sono‐TT8) that co‐delivers tirapazamine (TPZ) and siXkr8 using a TiO 2 ‐derived sonosensitizer functionalized with the tLyP‐1 peptide for active targeting of neuropilin‐1 (NRP‐1)‐overexpressing tumor cells. Upon ultrasound irradiation, Sono‐TT8 induces mitochondrial dysfunction and exacerbates local hypoxia to activate TPZ, while concurrently delivering siXkr8 to silence the Xkr8‐PS axis during chemotherapy‐induced apoptosis. This nanoinhibitor reprograms the tumor immunosuppressive microenvironment and reduces tumor growth. Furthermore, Sono‐TT8 exhibits superior tumor suppression and synergizes with αPD‐L1 to inhibit metastatic progression. Our work establishes a chemo‐immune checkpoint blockade strategy to overcome immune resistance in breast cancer, offering a nanosensitization approach compatible with multiple clinical treatment modalities.