ISG20L2 is a 3'-5' exoribonuclease with dual roles in ribosome biogenesis and immune regulation. Structurally, it contains an N-terminal nucleolar localization domain and a C-terminal catalytic exoribonuclease domain 1. In ribosome biogenesis, ISG20L2 is critical for processing precursor rRNAs, including 12S pre-rRNA maturation 1 and removal of the 3' external transcribed spacer during 18S and 28S rRNA maturation 2. Recently, ISG20L2 was identified as an RNA nuclease in activated T cells with preferential affinity for uridylated miRNA substrates, regulating expression of immunoregulatory molecules including PD-1, PD-L1, CTLA-4, and others 3. Clinically, ISG20L2 has significant disease relevance across multiple cancers. In multiple myeloma, ISG20L2 suppresses bortezomib sensitivity by competing with proteasome subunit PSMB5 for bortezomib binding, with ISG20L2 high expression correlating with treatment resistance 4. In hepatocellular carcinoma, elevated ISG20L2 expression is part of immune-related prognostic signatures associated with poor survival and represents an independent prognostic factor 56. Conversely, in breast cancer, ISG20L2 is identified as a hub gene upregulated in tumors with potential diagnostic and prognostic biomarker utility 7. In HCC, high miR-139-3p targeting ISG20L2 predicts better prognosis 8, suggesting ISG20L2 suppression may improve outcomes in specific contexts.