RPN1 Is Associated With Immunosuppression in Pan‐Cancer and Affects the Malignant Phenotype of Tumor

ABSTRACT Ribophorin 1 (RPN1), a key component of the oligosaccharyltransferase complex, is implicated in tumor progression through glycosylation‐mediated pathways, yet its pan‐cancer roles remain unexplored. This study presents a comprehensive multi‐omics analysis of RPN1 across 33 cancers such as sarcoma (SARC), integrating genomic, transcriptomic, and proteomic data from TCGA, GTEx, and CPTAC. RPN1 was significantly overexpressed in 14 malignancies and correlated with advanced tumor stages and poor prognosis in glioblastoma (GBM), lower‐grade glioma, SARC and hepatocellular carcinoma, validated in an independent glioma cohort ( n = 151). Genomically, RPN1 amplification linked to homologous recombination deficiency and elevated tumor mutational burden, suggesting a role in genomic instability. Critically, multiplex immunofluorescence demonstrates RPN1 overexpression colocalizes with CD206 + M2 macrophages in tumor microenvironments, while in vitro coculture experiments confirm RPN1‐dependent microglial recruitment and M2 polarization. RPN1 expression negatively correlates with CD8 + T cell infiltration and predicts resistance to chemotherapy (GBM, ovarian cancer) and immunotherapy (GBM, esophageal carcinoma), though it associates with PD‐1 inhibitor sensitivity in bladder cancer. Functional validation shows RPN1 knockdown suppresses proliferation, migration, and invasion in GBM cells. Pathway enrichment connects RPN1 to endoplasmic reticulum stress, glycosylation, DNA repair, and immune checkpoint regulation. These findings position RPN1 as a multimodal oncogenic driver promoting genomic instability, immunosuppressive microenvironment remodeling, and context‐dependent therapeutic vulnerabilities across cancers.