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

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.