ISG20 (interferon stimulated exonuclease gene 20) is an interferon-induced antiviral exoribonuclease that functions primarily as a host defense mechanism against viral infections. The protein exhibits 3'-5' exonuclease activity, primarily targeting single-stranded RNA substrates including viral RNAs 1. ISG20 demonstrates broad antiviral activity against various RNA viruses, with mechanisms involving both direct viral RNA degradation and inhibition of viral protein translation 1. However, its role extends beyond antiviral defense into cancer biology, where it exhibits complex dual functions. In glioma, ISG20 expression correlates with tumor grade and poor prognosis, promoting immune suppression through increased infiltration of immunosuppressive macrophages and neutrophils while suppressing adaptive immune responses 2. In breast cancer, ISG20 is regulated by HIF-1 and promotes cancer stemness through NANOG signaling activation, while simultaneously facilitating immune evasion by degrading STAT1 and IRF1 mRNAs, leading to decreased CXCL10 expression and impaired recruitment of CD8+ T cells 3. ISG20 also contributes to glioblastoma pathogenesis by facilitating tumor-associated macrophage polarization toward an immunosuppressive phenotype through the MET-STAT3-ISG20 axis 4. These findings highlight ISG20's potential as both a biomarker and therapeutic target in cancer treatment.