Unraveling the Biology of Interferon-Stimulated Genes: Mechanisms, Functions, and Clinical Implications

Interferon-stimulated genes (ISGs) constitute a central component of host defense, orchestrating antiviral, antibacterial, immunoregulatory, and cell fate-modulating responses. Traditionally recognized for their roles in restricting viral replication through well-characterized effectors such as Mx proteins, OAS, PKR, and the IFIT/IFITM families, ISGs are now understood to possess broader biological functions. Emerging evidence reveals their involvement in host-microbe interactions, tumor immunosurveillance, metabolic regulation, autophagy, and tissue repair. These diverse activities position ISGs as context-dependent immune regulators rather than mere antiviral effectors. This review synthesizes current knowledge on the canonical and noncanonical functions of representative ISG families, highlights their regulatory networks and evolutionary origins, and discusses their relevance to infectious, inflammatory, and malignant diseases. We further examine the therapeutic potential of targeting ISG pathways and explore their utility as biomarkers for diagnosis, prognosis, and treatment stratification. By integrating mechanistic insights with translational perspectives, this review provides a comprehensive understanding of ISGs as dynamic mediators at the interface of immunity, infection, and disease.