我们旨在研究泛素连接蛋白4在胃癌免疫治疗反应预测中的作用。对于接受复发后程序性死亡-1阻断治疗的胃癌患者进行了回顾性RNA测序和免疫组化分析。多重免疫组织化学技术确定了胃癌组织中的免疫细胞类型。我们使用免疫功能完整的615小鼠和免疫缺陷的裸小鼠进行肿瘤实验。与程序性死亡配体1相比，泛素连接蛋白4表达在反应者中显著升高（p < 0.05，虚假发现率 > 2.5），在预测程序性死亡-1抑制剂治疗反应方面稍微优越（曲线下面积：87.08 vs. 72.50）。泛素连接蛋白4高表达患者显示CD4+和CD8+ T细胞、T辅助细胞、单核细胞和巨噬细胞增加。泛素连接蛋白4过表达的小鼠前胃癌细胞在免疫功能完整小鼠中明显增强生长，而在免疫缺陷小鼠中没有增长。泛素连接蛋白4的上调或下调协同作用与程序性死亡配体1的蛋白和信使RNA水平有关。功能富集分析发现泛素连接蛋白4高表达的胃癌在Notch、JAK-STAT和WNT信号通路中有显著富集。泛素连接蛋白4促进Numb的降解，激活Notch信号通路并上调程序性死亡配体1。泛素连接蛋白4可能通过激活Notch信号通路并上调肿瘤细胞中的程序性死亡配体1表达，对胃癌的免疫逃避做出贡献。因此，泛素连接蛋白4可以作为胃癌中程序性死亡配体1抑制剂治疗反应的预测标志物。© 2023. Springer Nature Switzerland AG.

We aimed to investigate the role of ubiquilin-4 in predicting the immunotherapy response in gastric cancer.Retrospective RNA-sequencing and immunohistochemical analysis were performed for patients with gastric cancer who received programmed death-1 blockade therapy after recurrence. Multiplex immunohistochemistry identified immune cell types in gastric cancer tissues. We used immunocompetent 615 mice and immunodeficient nude mice to perform tumorigenic experiments.Ubiquilin-4 expression was significantly higher in responders (p < 0.05, false discovery rate > 2.5) and showed slight superiority over programmed death ligand 1 in predicting programmed death-1 inhibitor therapy response (area under the curve: 87.08 vs. 72.50). Ubiquilin-4-high patients exhibited increased CD4+ and CD8+ T cells, T follicular helper cells, monocytes, and macrophages. Ubiquilin-4-overexpressed mouse forestomach carcinoma cells showed significantly enhanced growth in immunocompetent mice but not in immunodeficient mice. Upregulation or downregulation of ubiquilin-4 synergistically affected programmed death ligand 1 at the protein and messenger RNA levels. Functional enrichment analysis revealed significant enrichment of the Notch, JAK-STAT, and WNT signaling pathways in ubiquilin-4-high gastric cancers. Ubiquilin-4 promoted Numb degaration, activating the Notch signaling pathway and upregulating programmed death ligand 1.Ubiquilin-4 may contribute to immune escape in gastric cancer by upregulating programmed death ligand 1 expression in tumor cells through Notch signaling activation. Thus, ubiquilin-4 could serve as a predictive marker for programmed death ligand 1 inhibitor therapy response in gastric cancer.© 2023. Springer Nature Switzerland AG.