摘要This study investigates the role of ERBB2 mutations in promoting recurrence and metastasis of non-muscle-invasive bladder cancer(NMIBC).Analysis of whole exome sequencing(WES)data from The Cancer Genome Atlas(TCGA)and the International Cancer Genome Consortium(ICGC)databases revealed a significant association between ERBB2 mutations and immune cell infiltration.To validate these findings,formalin-fixed,paraffin-embedded tumor tissues from patients with recurrent NMIBC were analyzed,with a focus on ERBB2 mutations.In addition,bladder cancer cell lines carrying wild type or mutant ERBB2 were established using clustered regularly interspaced short palindromic repeats(CRISPR)-associated protein 9(CRISPR/Cas9)technology.Functional experiments,including Western blotting,protein stability assays,and ubiquitination analyses,demonstrated that ERBB2 mutations promote hypoxia-inducible factor-1(HIF-1)phosphorylation,leading to its stabilization and enhancing the proliferative,migratory,and invasive capacities of tumor cells.Furthermore,flow cytometry,5-ethynyl-2'-deoxyuridine(EdU),Cell Counting Kit-8(CCK-8),and Transwell assays confirmed the impact of these mutations on cellular behavior,while drug sensitivity assays indicated increased sus-ceptibility of ERBB2-mutant cells to therapeutic agents.In vivo studies using mouse models further supported these findings,showing that ERBB2 mutations promote tumor growth,metastasis,and macrophage infiltration.Collectively,these results suggest that ERBB2 mutations drive NMIBC pro-gression by stabilizing HIF-1 through phosphorylation,thereby facilitating tumor development and immune modulation,and underscore the potential of ERBB2 as a therapeutic target for preventing NMIBC recurrence and metastasis.