Integrative pan-cancer analysis suggests ISG15-linked immune and phosphoproteomic divergence between KIRC and KICH

Background: Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like modifier induced by inflammatory cues, yet its functional relevance in cancer remains unclear and context dependent. Although frequently used as an interferon marker, whether ISG15 reflects effective antitumor immunity or dysfunctional immune states across cancers has not been systematically resolved. Methods: We performed an integrative pan-cancer analysis using TCGA, CPTAC, GEO, and immunotherapy and single-cell RNA-seq cohorts. ISG15 was examined at transcriptomic, proteomic, epigenetic, genetic, immune-infiltration, and phosphoproteomic levels. Survival-modeling, mutation and copy-number analyses, pathway-enrichment, protein-protein interaction networks, and kinase enrichment were used to define functional associations, with focused comparisons between renal clear cell carcinoma (KIRC) and chromophobe carcinoma (KICH). Results: ISG15 was upregulated in all studied cancers but downregulated in KICH. Its prognostic associations were bidirectional, correlating with poor survival in KIRC, LIHC, COAD, and LGG, yet favorable outcomes in SKCM, MESO, and OV. In KIRC, high ISG15 was associated with early promoter hypomethylation, interferon signaling, immune infiltration, T-cell exhaustion signatures, and broad immune-associated phosphokinase activity. In contrast, KICH showed preserved methylation, weak interferon coupling, limited immune engagement, and phosphoproteomic enrichment of structural and trafficking pathways. Genetic alterations and deep deletions of ISG15 were associated with shorter progression-free survival. Conclusion: This study indicates that ISG15 is associated with dysfunctional immune states rather than a direct effector of tumor control. These findings highlight ISG15 as a context-specific biomarker whose functional impact likely depends on tumor type and microenvironment, warranting further mechanistic and experimental validation.