The Role of ISG15 in Cancer Biology: Systematic Evaluation of ISG15 Expression and Its Molecular Interactions in a Pan-Cancer Context

ISG15’s dual role in cancer biology still remains unclear. One major area requiring further investigation is the molecular mechanisms underlying ISG15’s pro- and anti-tumorigenic roles in different cancer types. In this study, we try to find the probable pathways that could be influenced by ISG15 in different cancers. ISG15, a ubiquitin-like protein is essential in the post-translational modification ISGylation, which involves a series of E1, E2, and E3 enzymes. During viral infections, ISG15 stimulates Type I interferon production and affects key proteins such as STAT1, JAK-1, MDA-5, Mx1, and RIG-1, thus impacting both host immunity and viral evasion strategies. Furthermore, ISG15 exhibits a complex role in cancer, acting as either a tumor suppressor or an oncogene depending on its state—free or conjugated. Intracellular free ISG15 affects protein stability, while extracellular ISG15 has immunomodulatory effects. Despite its significant role in immune regulation and cancer biology, the exact mechanisms through which ISG15 influences cancer progression remain to be fully elucidated. In this study, we examined ISG15’s role in tumor development and progression across 22 cancer types by integrating data from high-throughput databases including TCGA, GTEx, and CPTAC. We evaluated ISG15 expression at both mRNA and protein levels, noting increased mRNA expression in all cancer types except Kidney Chromophobe (KICH) and elevated protein levels in nine out of ten analyzed cancer types, with the exception of liver carcinoma. Analysis of TP53 mutations showed reduced ISG15 mRNA levels in KICH regardless of mutation status. Correlation analyses identified seven highly correlated genes—IFI35, IFI44, OASL, MX1, RSAD2, OAS2, and IRF7 involved in ISG15 downstream signaling. Protein-protein interaction networks revealed hub genes including STAT1, IFIT1, IFIT2, and OASL, which are crucial in cancer pathogenesis and warrant in-depth studies for therapeutic targets and drug repurposing.