TP53 Loss Elevates NF‐κB‐IFN‐β‐MHC‐Ia Signaling to Promote NK Cell Resistance in Osteosarcoma

TP53 inactivation is a key event in osteosarcoma (OS) development and underlies its aggressiveness, yet its role in tumor-immune interactions remains poorly understood. Here, we investigate how p53 loss alters osteosarcoma susceptibility to natural killer (NK) cell-mediated cytotoxicity using OS cell lines and stem cell-derived OS-associated models. We found that TP53 loss in human osteosarcoma cell lines dysregulates NK cell regulatory ligands, specifically upregulating MHC-Ia to confer resistance to NK cell killing. Single-cell RNA sequencing of clinical specimens reveals mesenchymal stem cells (MSCs) is associated with OS development. Using human embryonic stem cell (hESC)-derived MSCs, the study shows that TP53 loss also drives MHC-Ia overexpression and NK cell resistance via activation of the cytosolic dsDNA-NF-κB-IFN-β axis. Syngeneic mouse models confirmed that p53 loss results in more aggressive tumors with reduced NK cell infiltration than wild-type controls. Clinically, impaired p53 function correlates with elevated MHC-Ia expression and type I IFN signaling. These findings uncover that a TP53 loss-triggered NF-κB-IFN-β-MHC-Ia axis contributes to NK cell resistance in OS development and highlight its potential as a critical therapeutic target for early intervention.