Oncogenic viruses rewire the epigenome in human cancer

Abstract

Viruses contribute to approximately 15-20% of global cancer cases, yet the full spectrum of their oncogenic mechanisms continues to be uncovered. Beyond the classical roles of genome integration, chronic inflammation, and immune evasion, mounting evidence reveals that oncogenic viruses-including the human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Human T-cell leukemia virus type 1 (HTLV-1)-profoundly reshape the host epigenome to establish persistent infection and promote tumorigenesis. These viruses orchestrate widespread and durable changes in DNA methylation, histone modification, chromatin accessibility, and non-coding RNA expression, silencing tumor suppressors, deregulating oncogenic pathways, and inducing stemness-like phenotypes. In this review, we provide a comprehensive synthesis of how distinct oncogenic viruses modulate the epigenetic landscape across tissue contexts, with a focus on cervical, hepatic, and lymphoepithelial cancers. We also explore how these virus-induced epigenetic "scars" may persist after viral clearance and highlight recent advances in therapeutic targeting. Emerging therapeutic strategies that integrate oncolytic virotherapy, epigenetic drugs, and immune modulation through combinational therapy offer synergistic mechanisms to overcome immune resistance and epigenetic silencing in virus-induced cancers. These integrated approaches hold transformative potential for more durable and targeted treatment outcomes.

Keywords: cancer; drugs; epigenome; immune modulation; oncogenic virus; oncolytic virotherapy.

Figure 1

Epigenetic reprogramming by oncogenic viruses in human cancer. This schematic summarizes how oncogenic viruses such as HPV, EBV, HBV, HCV, and HTLV-1 reshape the host epigenome to promote tumorigenesis. Key viral proteins modulate chromatin accessibility and gene expression by altering DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA expression. Enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), histone deacetylases (HDACs), and demethylases (e.g., TETs, KDMs) dynamically write or erase epigenetic marks. These virus-induced epigenetic changes silence tumor suppressor genes, activate oncogenic pathways, and contribute to immune evasion and cancer progression—even after viral clearance.

Figure 2

Dual mechanism of tumor elimination by oncolytic viruses. Oncolytic viruses exert anti-tumor effects through both direct and immune-mediated mechanisms. Upon selective infection of cancer cells, they replicate and induce immunogenic cell death, releasing danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). These signals activate dendritic cells (DCs), which present tumor antigens and prime cytotoxic T lymphocytes (CTLs). The activated CTLs then infiltrate the tumor microenvironment and mediate additional tumor cell killing, amplifying the therapeutic response.