Multi-omics and experimental validation reveal ISG20L2 as a potential pro-oncogenic regulator in gastric cancer
Gastric cancer is a major malignancy with molecular heterogeneity and limited biomarkers for risk stratification and therapeutic guidance. Interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2), a regulator of ribosome biogenesis, has been implicated in tumor progression, but its relevance in gastric cancer is poorly defined. This study aimed to characterize the potential pro-oncogenic and immune relevance of ISG20L2 in gastric cancer. Public multi-omics datasets and two single-cell RNA-sequencing cohorts were used to evaluate ISG20L2 expression and its associations with molecular features, tumor functional states, immune infiltration, and immunotherapy-related characteristics. Protein expression was validated in gastric cancer cell lines and nine paired clinical tissues, and functional effects of ISG20L2 knockdown were assessed in AGS and HGC-27 cells. ISG20L2 was significantly upregulated in gastric cancer and inversely correlated with promoter methylation. Single-cell analysis showed predominant enrichment of ISG20L2 in exhausted CD8+ T cells. High ISG20L2 expression was closely associated with cell-cycle activity, immune infiltration, PD-L1 expression and predicted immunotherapy response. Experimentally, ISG20L2 protein was elevated in gastric cancer cell lines and tumor tissues. ISG20L2 knockdown markedly suppressed proliferation, clonogenicity, migration and invasion in both AGS and HGC-27 cells. ISG20L2 is aberrantly upregulated and associated with malignant biological features and immune-related characteristics in gastric cancer, supporting its potential role as a pro-oncogenic regulator and a candidate molecular indicator requiring further clinical validation.