BackgroundGJB2 plays an essential role in the growth and progression of several cancers. However, asystematic pan-cancer analysis of GJB2 is lacking. Therefore, in this study, we performed a comprehensive pan-cancer analysis to determine the potential role of GJB2 in prognostic prediction and cancer immunotherapy response.MethodsThe differential expression of GJB2 in the tumor and adjacent normal tissues of various cancer types was analyzed using the TIMER, GEPIA, and Sangerbox databases. GEPIA and Kaplan–Meier plotter databases were used to analyze the survival outcomes based on GJB2 expression levels in pan-cancer. Furthermore, the association of GJB2 expression with the immune checkpoint (ICP) genes, tumor mutational load (TMB), microsatellite instability (MSI), neoantigens, and tumor infiltration of immune cells was analyzed usingviathe Sangerbox database. The cBioPortal database was used to determine the characteristics ofGJB2gene alterations in the cancer tissues. The STRING database was used to identify the GJB2-binding proteins. GEPIA database was used to identify the GJB2 co-expressed genes. DAVID was used to perform the functional enrichment analysis of gene ontology (GO) terms and KEGG pathways associated with GJB2. Finally, the mechanistic role of GJB2 in pancreatic adenocarcinoma (PAAD) was analyzed using the LinkedOmics database.ResultsTheGJB2gene was highly expressed in a variety of tumors. Furthermore, GJB2 expression levels showed significant positive or negative association with the survival outcomes in various cancers. GJB2 expression levels cor related with tumor mutational burden, microsatellite instability, neoantigens, and tumor infiltration of immune cells in multiple cancers. This suggested that GJB2 played a critical role in the tumor microenvironment. Functional enrichment analysis showed that the biological role of GJB2 in tumors included modulation of gap junction-mediated intercellular transport, regulation of cell communication by electrical coupling, ion transmembrane transport, autocrine signaling, apoptotic signaling pathway, NOD-like receptor signaling pathway, p53 signaling pathway, and PI3K-Akt signaling pathway.ConclusionsOur study demonstrated that GJB2 played a significant role in tumorigenesis and tumor immunity in multiple cancers. Furthermore, GJB2 is a potential prognostic biomarker and a promising therapeutic target in multiple types of cancers.