Targeting the YAP‐BST2 Axis Overcomes Intrinsic Anti‐PD‐1 Resistance in Metastatic Gastric Cancer

ABSTRACT Intrinsic resistance to anti‐PD‐1 immunotherapy remains a major obstacle in treating metastatic gastric cancer (GC), particularly in tumors harboring concurrent YAP hyperactivation and TP53 loss. Here, using a genetically engineered mouse model with conditional YAP hyperactivation and Tp53 deletion in gastric Atp4b + cells (AYP), we show this “double‐hit” alone suffices to recapitulate human refractory GC, including histopathological heterogeneity, multi‐organ metastasis, and intrinsic PD‐1 resistance. We identified BST2 as a direct YAP‐TEAD transcriptional target. In human GC, BST2‐high tumor correlates with poor anti‐PD‐1 response. Mechanistically, tumor cell‐derived BST2 engages the inhibitory receptor PIRA2 on neutrophils and liver Kupffer cells, instructing an immunosuppressive, pro‐metastatic phenotype that inhibits T cells antitumor response and confers PD‐1 resistance. Therapeutically, dual BST2/PD‐1 blockade in the AYP model suppresses primary tumor growth and eradicates established liver metastases. Thus, YAP activation, cooperating with TP53 loss, fuels metastatic GC and immunotherapy resistance via BST2 induction.