Virus-encoded circular RNAs in human cancer: mechanisms and clinical implications

Circular RNAs (circRNAs) are covalently closed RNA molecules generated mainly through back-splicing. Their resistance to exonuclease-mediated degradation, cell-type specificity, and regulatory versatility make them important participants in both host and viral biology. Since the initial demonstration that circular DNA tumor viruses produce abundant circRNAs, an expanding repertoire of virus-encoded circular RNAs (viro-circRNAs) has been identified in Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and related animal tumor viruses. Accumulating evidence indicates that viro-circRNAs are not passive transcriptional by-products; rather, they function as miRNA sponges, RNA-binding protein scaffolds, modulators of RNA stability and transcription, epigenetic or epitranscriptomic regulators, and in selected cases, templates for viral peptide or oncoprotein translation. Recent studies have refined this field by revealing noncanonical herpesvirus-driven circRNA biogenesis, EBV circRPMS1-mediated METTL3 activation and p53 interaction, hypoxia-induced EBV circLMP2A-driven angiogenesis, HPV16 circE7-mediated immune evasion through promoter histone modification, HBV-derived circRNA signaling in hepatocellular carcinoma, and HCV-derived circRNAs that support viral RNA amplification. In this review, we synthesize current evidence using a mechanistic and clinically oriented framework: first defining viro-circRNA biogenesis and validation, then summarizing virus- and cancer-specific expression patterns, followed by a detailed analysis of direct tumor-cell mechanisms, tumor microenvironment remodeling, biomarker potential, therapeutic opportunities, and unresolved challenges. This framework is intended to move the discussion beyond descriptive cataloguing and toward testable hypotheses for translational viro-circRNA research.