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Here, we investigate how p53 loss alters osteosarcoma susceptibility to natural killer (NK) cell\u2010mediated cytotoxicity using OS cell lines and stem cell\u2010derived OS\u2010associated models. We found that\n                    <jats:italic>TP53<\/jats:italic>\n                    loss in human osteosarcoma cell lines dysregulates NK cell regulatory ligands, specifically upregulating MHC\u2010Ia to confer resistance to NK cell killing. Single\u2010cell RNA sequencing of clinical specimens reveals mesenchymal stem cells (MSCs) is associated with OS development. Using human embryonic stem cell (hESC)\u2010derived MSCs, the study shows that\n                    <jats:italic>TP53<\/jats:italic>\n                    loss also drives MHC\u2010Ia overexpression and NK cell resistance via activation of the cytosolic dsDNA\u2010NF\u2010\u03baB\u2010IFN\u2010\u03b2 axis. Syngeneic mouse models confirmed that p53 loss results in more aggressive tumors with reduced NK cell infiltration than wild\u2010type controls. Clinically, impaired p53 function correlates with elevated MHC\u2010Ia expression and type I IFN signaling. These findings uncover that a\n                    <jats:italic>TP53<\/jats:italic>\n                    loss\u2010triggered NF\u2010\u03baB\u2010IFN\u2010\u03b2\u2010MHC\u2010Ia axis contributes to NK cell resistance in OS development and highlight its potential as a critical therapeutic target for early intervention.\n                  <\/jats:p>","DOI":"10.1002\/advs.77726","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:51:28Z","timestamp":1789131088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TP53 Loss Elevates NF\u2010\u03baB\u2010IFN\u2010\u03b2\u2010MHC\u2010Ia Signaling to Promote NK Cell Resistance in Osteosarcoma"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4392-9578","authenticated-orcid":false,"given":"Guihui","family":"Qin","sequence":"first","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision 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