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BackgroundInterferon-stimulated gene 15 (ISG15) is a small ubiquitin-like protein that can be conjugated to its target proteins through an enzymatic cascade known as ISGylation, thereby altering their function. Elevated levels of free ISG15 (non-conjugated) and ISGylation are observed in several cancer types, including medulloblastoma (MB) a malignant pediatric cerebellar tumor categorized into four molecular subgroups: Wingless, Sonic Hedgehog, Subgroup 3 (G3), and Subgroup 4 (G4). However, ISG15 gene expression in MB remains unexplored. In this study, we evaluated the ISG15 protein levels, the expression of the ISG15 and ISGylation system, and interferon gamma signaling mediators in human MB samples to propose the role of ISG15 in this tumoral context.MethodsISG15 expression in MB samples was comparatively analyzed against normal tissue using the Oncopression database. Expression levels were further assessed in various pediatric tumors within the Childhood Brain Tumor Tissue Consortium dataset via the University of Alabama at Birmingham Cancer Data Analysis Portal database. ISG15 protein abundance in MB samples was then evaluated via immunohistochemistry on a tumor tissue microarray. To broaden the analysis, ISG15 expression was profiled across multiple MB cell lines using the R2 Genomics Analysis and Visualization Platform. Finally, to determine clinical significance, the association between ISG15 expression and patient survival was assessed using Kaplan-Meier analysis.ResultsISG15 expression was significantly lower in MB samples than in other pediatric tumors (p < 0.05) and normal tissue (p < 0.0001). Immunohistochemical analysis further confirmed a marked reduction in ISG15 protein abundance in MB samples compared to healthy tissue (p < 0.001). Elevated ISG15 levels correlated with improved survival outcomes in the G3 and G4 subgroups (p < 0.05).ConclusionISG15 is downregulated in MB tissues compared to controls. High ISG15 expression within the G3/G4 MB subgroups correlates with prolonged survival, suggesting a potential tumor-suppressive function. These results collectively indicate that ISG15 may serve as a valuable prognostic biomarker for G3/G4 MB patients.