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Through single\u2010cell database mining and in vitro analysis, we demonstrate that chemotherapy upregulates Xkr8 expression and promotes phosphatidylserine (PS) externalization, which mediates macrophage\u2010 and dendritic cell (DC)\u2010intrinsic immunosuppression. To address this, we fabricate an ultrasound\u2010activated nanoinhibitor (Sono\u2010TT8) that co\u2010delivers tirapazamine (TPZ) and siXkr8 using a TiO\n                    <jats:sub>2<\/jats:sub>\n                    \u2010derived sonosensitizer functionalized with the tLyP\u20101 peptide for active targeting of neuropilin\u20101 (NRP\u20101)\u2010overexpressing tumor cells. Upon ultrasound irradiation, Sono\u2010TT8 induces mitochondrial dysfunction and exacerbates local hypoxia to activate TPZ, while concurrently delivering siXkr8 to silence the Xkr8\u2010PS axis during chemotherapy\u2010induced apoptosis. This nanoinhibitor reprograms the tumor immunosuppressive microenvironment and reduces tumor growth. Furthermore, Sono\u2010TT8 exhibits superior tumor suppression and synergizes with \u03b1PD\u2010L1 to inhibit metastatic progression. Our work establishes a chemo\u2010immune checkpoint blockade strategy to overcome immune resistance in breast cancer, offering a nanosensitization approach compatible with multiple clinical treatment modalities.\n                  <\/jats:p>","DOI":"10.1002\/advs.77635","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:09:53Z","timestamp":1788930593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ultrasound\u2010Activated Nanoinhibitors Blocking the Chemo\u2010Immune Checkpoint to Overcome Chemotherapy\u2010Induced Immune Resistance"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4423-7172","authenticated-orcid":false,"given":"Yunfan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Ultrasound The Second Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Ultrasound Molecular Imaging and Therapy 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Ultrasound Molecular Imaging and Therapy Institute of Ultrasound Imaging Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Second Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Ultrasound Molecular Imaging and Therapy Institute of Ultrasound Imaging Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Second Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Ultrasound Molecular Imaging and Therapy Institute of Ultrasound Imaging Chongqing Medical University  Chongqing 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