The yin and yang of ISGylation: a bifunctional regulator of antiviral defense and cancer progression with therapeutic implications

Abstract

ISGylation has traditionally been examined in the context of antiviral immunity, where it is widely recognized as a protective interferon-stimulated response. This protective dimension may be considered the “yang” of ISGylation, reflecting its role in viral restriction, immune defense, and maintenance of cellular homeostasis. Numerous reviews have emphasized this antiviral and beneficial function while contrasting it with emerging evidence implicating ISGylation in cancer-associated pathways, where its effects remain less clearly defined, often context-dependent, and potentially pathogenic. This disease-promoting dimension may represent the “yin” of ISGylation, in which the same regulatory system may contribute to oncogenic signaling, immune evasion, tumor–stromal interactions, or cancer cell cooperation. However, existing literature has largely treated these opposing roles as parallel but separate phenomena. This review proposes a unifying perspective by examining ISGylation as a dynamic regulatory system whose functional outcome is shaped by cellular context, disease state, and intercellular communication. Recent findings are synthesized on the dual activities of ISG15, both as an intracellular ubiquitin-like modifier and as a free, secreted molecule with cytokine-like properties. While intracellular ISGylation affects viral restriction, immune signaling, and oncogenic pathways, increasing evidence suggests that unconjugated ISG15 can be released from cells and participate in immune modulation beyond the cell of origin. Notably, this review highlights the underexplored role of exosome-mediated ISG15 trafficking as a potential mechanism of cell-to-cell communication. This mode of signaling may be particularly relevant in the tumor microenvironment, where ISGylation could influence immune evasion, tumor–stromal crosstalk, and cooperative cancer cell behavior in ways that are not yet fully appreciated. By integrating intracellular and extracellular dimensions, this review reframes the “protective versus pathogenic” dilemma as a yin–yang regulatory balance and suggests that ISGylation’s therapeutic potential may be embedded in its intertwined intracellular and intercellular communication networks in viral infection and cancer.