One of the most stubborn puzzles in cancer immunotherapy may have just cracked open. In a study published in Advanced Science, researchers report the construction of a genetically engineered mouse model of gastric cancer that, for the first time, faithfully reproduces the defining features of the human disease at its most lethal: profound histological diversity, rampant multi-organ metastasis, and an almost complete refusal to respond to anti-PD-1 immunotherapy. Using this model, the team uncovered a previously hidden molecular circuit in which the oncogenic co-activator YAP switches on a protein called BST2 on the surface of tumor cells, which in turn reprograms neutrophils and liver-resident macrophages into immunosuppressive enforcers. Blocking both BST2 and PD-1 simultaneously did something that single-agent immunotherapy could not: it shrank primary gastric tumors and completely eliminated visible liver metastases in every treated animal.
The clinical backdrop makes the advance urgent. Gastric cancer remains one of the world’s deadliest malignancies, characterized by molecular heterogeneity, a high propensity for metastatic spread, and frequent therapeutic resistance. Immune checkpoint blockade, particularly antibodies against the PD-1/PD-L1 axis, has transformed outcomes in several tumor types, yet in gastric cancer the response rates stubbornly remain below 30 percent, with a substantial fraction of patients showing intrinsic resistance from the very first dose. The researchers turned to cancer genetics for an explanation. A significant subset of gastric cancers, especially those defined by chromosomal instability, carry two simultaneous alterations: loss of the tumor suppressor TP53 and hyperactivation of YAP, the transcriptional co-activator that serves as the main effector of the Hippo signaling pathway. YAP1 is amplified in roughly 18 percent of human gastric cancers, and the combination of YAP activation with p53 loss correlates clinically with aggressive, refractory disease. Whether this genetic pairing was a mere correlation or a true causal driver of immunotherapy resistance was the central question the study set out to answer.
To probe that question, the investigators engineered a sophisticated mouse model they call AYP. These animals carry a conditional, constitutively active YAP1 mutant, designated Yap1-6A, in which six phosphorylation sites were mutated so the protein resists degradation, together with floxed Tp53 alleles. Both alterations were activated specifically in the Atp4b-expressing parietal cell lineage of the stomach, which encompasses parietal cell progenitors, pre-parietal cells, and mature acid-producing cells. After tamoxifen induction, the mice developed invasive gastric adenocarcinoma within two to three months, with a median survival of 131 days. Crucially, the model demonstrated biological synergy rather than mere additivity: mice with YAP activation alone or p53 loss alone failed to develop gastric cancer even ten months after induction, while the double-hit configuration produced fully penetrant, aggressive malignancy. Histopathological examination revealed the full spectrum of human disease, including well-differentiated intestinal-type tumors, poorly differentiated signet-ring cell carcinomas of the diffuse type, and mixed forms, all accompanied by dense immune infiltration.
The metastatic behavior of the model proved equally faithful to the human condition. By three to four months after induction, the majority of AYP mice had disseminated disease involving the gastric lymph node, diaphragm, liver, pancreas, mediastinal lymph node, and lung, with metastatic incidence rates recorded for each organ across the cohort. Fluorescent labeling confirmed that the metastatic lesions originated from the Atp4b-lineage tumor cells. When the researchers treated these mice with anti-PD-1 antibodies for three weeks, the results were sobering but clinically familiar: stomach weights were unchanged, metastatic incidence and morphology were unaltered, and histopathology confirmed no therapeutic response. Immune profiling showed only a modest reduction in neutrophils, regulatory T cells, and group 3 innate lymphoid cells. In other words, the AYP tumors were intrinsically resistant to PD-1 blockade despite being what immunologists would call hot tumors, densely infiltrated with immune cells that should, in principle, be attackable.
To find the mechanism, the team performed single-cell RNA sequencing on nearly 50,000 high-quality cells harvested from the stomach, gastric lymph node, and visible liver and lung metastases of AYP mice and matched wild-type controls. The analysis identified three distinct tumor cell clusters, and gene set variation analysis revealed strong enrichment of Hippo signaling, YAP/TAZ target gene signatures, epithelial-mesenchymal transition features, and immunosuppression programs. When the researchers compared the mouse tumor transcriptomes with a single-cell dataset from 26 gastric cancer patients, the AYP tumor cells correlated closely with human poorly differentiated gastric adenocarcinoma, including signet-ring cell carcinoma, with high correlation coefficients for signature genes such as OLFM4, PLA2G2A, and ENO1. A dominant feature of the microenvironment, at both primary and metastatic sites, was a pronounced infiltration of neutrophils displaying characteristics of polymorphonuclear myeloid-derived suppressor cells, key systemic mediators of immunosuppression that are clinically associated with poor immunotherapy responses. Depleting neutrophils substantially inhibited tumor development and metastasis, establishing these cells as essential players rather than bystanders.
The search for the molecular bridge between YAP and the suppressive microenvironment converged on BST2, or bone marrow stromal cell antigen 2. Integrated analysis of tumor cell signature genes and genes downregulated after YAP1 knockout identified BST2 as a top candidate. Immunofluorescence confirmed that BST2 was co-expressed with the tumor marker KRT7 specifically within tumor tissue and was undetectable in normal gastric epithelium. Clinically, the pattern was striking: both BST2 and YAP1 transcription were markedly higher in gastric cancer patients whose disease progressed on anti-PD-1 therapy than in those achieving complete or partial responses, mirroring established immunosuppressive markers such as NR4A1 and CD55. Mechanistically, the team showed that deleting YAP1 with CRISPR/Cas9 significantly reduced both BST2 mRNA and surface protein levels, and CUT&RUN assays demonstrated direct binding of the YAP1-TEAD4 transcriptional complex to the Bst2 promoter, formally establishing BST2 as a direct YAP target gene.
Functional experiments then revealed BST2 as a genuine immune checkpoint operating on innate immune cells. Deleting BST2 from AYP tumor cells had only a marginal effect on proliferation in a dish but significantly impaired tumor formation and growth in living mice, accompanied by reduced numbers of tumor-infiltrating neutrophils and lower PD-L1 expression on those cells, decreased exhaustion of natural killer and CD4 T cells, and increased production of the cytotoxic enzyme Granzyme B. Ligand-receptor interaction analysis pointed to BST2 engaging a receptor called PIRA2, the murine ortholog of human leukocyte immunoglobulin-like receptors, which is highly expressed on neutrophils. Co-immunoprecipitation and protein truncation experiments mapped the physical interface: the coiled-coil domain of BST2 directly binds the Ig-like domain of PIRA2 through two distinct contact surfaces. Co-culture assays confirmed that AYP tumor cells drive bone marrow cells toward an immunosuppressive SiglecF-positive, PD-L1-positive neutrophil phenotype, an effect abolished either by BST2 knockout or by a BST2-blocking antibody.
The liver emerged as a particularly instructive battleground. Kupffer cells, the resident macrophages of the liver, also express high levels of PIRA2, and transcriptional profiling showed that AYP mice accumulated immunosuppressive Kupffer cell subsets at the expense of immunostimulatory ones. In co-culture, AYP tumor cells expanded the pool of CD11b-high Kupffer cells and upregulated the suppressive markers Arg1 and PD-L1, effects again dependent on BST2. In a liver metastasis model based on splenic injection of tumor cells, BST2 deficiency significantly prolonged host survival, reduced metastatic tumor burden, and boosted Granzyme B production by liver CD8 T cells, indicating reinvigorated anti-tumor immunity. The therapeutic culmination came in the spontaneous AYP model itself: combining anti-BST2 with anti-PD-1 antibodies reduced stomach weights by nearly 30 percent compared with anti-PD-1 alone, restored glandular tissue architecture, and, most strikingly, completely eradicated visible liver metastases in all treated animals while suppressing lymph node spread beyond what either agent achieved alone.
The implications reach beyond gastric cancer. BST2 was upregulated in tumors from resistant patients across multiple cancer types, suggesting it may function as a pan-tumor marker of anti-PD-1 failure, and its known role in suppressing plasmacytoid dendritic cells offers a plausible explanation for how anti-BST2 therapy also curbed lymph node metastases. The study also raises tantalizing questions about the microbial dimension, since bacteria such as Helicobacter pylori and Streptococcus anginosus can activate YAP signaling in gastric epithelium, potentially sustaining the BST2-driven resistance program. Significant work remains before patients benefit: the downstream signaling events of BST2-PIRA2 engagement are not fully mapped, structural studies of the interaction are needed to design high-affinity blockers, and humanized anti-BST2 antibodies must now prove themselves in patient-derived models. Still, for the large population of patients whose hot, immune-infiltrated gastric tumors inexplicably shrug off PD-1 blockade, the identification of a druggable YAP-BST2 axis offers something they have not had before: a mechanistic explanation and a concrete combination strategy to test in the clinic.
Subject of Research: YAP-BST2-mediated intrinsic resistance to anti-PD-1 immunotherapy in metastatic gastric cancer
Article Title: Targeting the YAP‐BST2 Axis Overcomes Intrinsic Anti‐PD‐1 Resistance in Metastatic Gastric Cancer
Article References: Zhang, W., Wang, S., Wang, M., Yu, R., Yue, J., Shao, L., Zhang, H., Zhu, M., Tian, L., Cheng, S., Qin, W., Tang, Y., Han, Y., Wang, W., An, L., Meng, Y., Jiao, S., & Zhou, Z. (2026). Targeting the YAP‐BST2 Axis Overcomes Intrinsic Anti‐PD‐1 Resistance in Metastatic Gastric Cancer. Advanced Science, Article e77708. https://doi.org/10.1002/advs.77708
Image Credits: AI Generated
DOI: 10.1002/advs.77708
Keywords: gastric cancer, immunotherapy resistance, YAP, TP53, BST2, PD-1, neutrophils, Kupffer cells, PIRA2, Hippo pathway, mouse model, liver metastasis
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Tags: BST2gastric cancergastric cancer immune evasiongenetically engineered mouse models for gastric cancerHippo pathwayimmunotherapy combination strategies for gastric cancerImmunotherapy ResistanceKupffer cellsliver metastasisliver metastasis in gastric cancermechanisms of immunotherapymolecular mechanisms of gastric tumor immune resistancemouse modelneutrophil reprogramming in cancerneutrophilsPD-1PIRA2resistance to PD-1 immunotherapy in gastric cancerrole of BST2 in tumor immune escapetargeting immunosuppressive myeloid cells in gastric cancerTP53tumor microenvironment in gastric cancerYAPYAP-BST2 immune suppression pathway
