One of the most studied epigenetic changes in HPV-transformed cells is hypermethylation of cell adhesion molecule 1 (CADM1), death-associated protein kinase 1 (DAPK1), and retinoic acid receptor beta (RARB) gene promoters (Laengsri et al., 2018). These changes, often mediated by DNMT overexpression, result in gene silencing that facilitates epithelial–mesenchymal transition (EMT) and immune evasion. Notably, cyclin-dependent kinase inhibitor 2A (CDKN2A) and L1 cell adhesion molecule (L1CAM) hypermethylation correlates with tumor progression and invasiveness (Weiss et al., 2022; Ogiwara and Kohno, 2012).

HPV oncoproteins also disrupt histone modification landscapes. E7 recruits HDAC1/2 and EZH2, the methyltransferase component of PRC2, promoting repressive H3K27me3 marks on tumor suppressors​ (Soto et al., 2017; Liu et al., 2023; Durzynska et al., 2017). E6 suppresses p300/CBP HATs, lowering acetylation at H3 and H4, leading to condensed chromatin and silenced genes (Ibrahim et al., 2022).

HPV infection induces extensive non-coding RNA (ncRNA) deregulation. It downregulates tumor-suppressive miRNAs like miR-34a, miR-143, and miR-145, affecting the PI3K/AKT and Wnt/β-catenin pathways (Ranga et al., 2023). These miRNAs are often silenced via epigenetic repression driven by E6/E7 (Lajer et al., 2012; Castro-Oropeza and Piña-Sánchez, 2022). Simultaneously, HPV upregulates oncogenic long non-coding RNA (lncRNAs) such as HOTAIR and MALAT1, which modulate chromatin modifiers and sponge tumor-suppressive miRNAs, reinforcing oncogenic signaling (Castro-Oropeza and Piña-Sánchez, 2022).

The reversibility of epigenetic modifications makes them attractive targets for therapy. Biomarkers like CADM1 methylation are being tested in non-invasive screening and epigenetic drugs—such as DNMTis (e.g., 5-azacytidine; NTC01349959 and NCT01105377) and HDACis (e.g., romidepsin; NCT04639843)—are in preclinical and early-phase clinical trials (Dueñas-González et al., 2005; Poreba et al., 2011; Zhang et al., 2022; Li et al., 2014). Notably, targeting EZH2 or restoring miR-34a can enhance the efficacy of immune checkpoint inhibitors, highlighting the promise of combined epigenetic–immunotherapeutic approaches (Tao et al., 2022).

EBV, a ubiquitous gammaherpesvirus, is implicated in the development of various lymphoid and epithelial malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), nasopharyngeal carcinoma (NPC), and EBV-associated gastric carcinoma (EBVaGC). EBV’s oncogenic capacity is largely attributed to its profound ability to reprogram host epigenetic landscapes to promote viral latency, immune evasion, and cellular transformation (Shareena and Kumar, 2023; Leong and Lung, 2021; Scott, 2017). EBV persists in the host in either latent or lytic forms. During latency, viral gene expression is restricted and epigenetically regulated to avoid immune detection. The latency program includes the expression of genes such as EBNA1, LMP1, LMP2A/B, EBERs, and BARTs, depending on latency type (I–III). These genes not only maintain the viral episome but also manipulate host epigenetic mechanisms to modulate transcription of both viral and host genomes (Shareena and Kumar, 2023; Scott, 2017; Yau et al., 2014).

EBV-infected cells exhibit marked promoter hypermethylation of tumor suppressor genes such as CDH1, PTEN, p16, DAPK, and RASSF1A. This is particularly evident in EBVaGC and NPC, which show a CpG island methylator phenotype (CIMP) characterized by dense promoter methylation across multiple gene loci (Niller et al., 2016; Cao et al., 2021; Yau et al., 2014). Latent proteins LMP1 and LMP2A drive these effects through the upregulation of DNMT1, DNMT3A, and DNMT3B, leading to transcriptional silencing of tumor suppressors (Yau et al., 2014; Scott, 2017; Okano, 2000).

Beyond DNA methylation, EBV also manipulates histone modifications. The viral oncoproteins (e.g., EBNA2, EBNA3C, LMP1) recruit histone-modifying complexes such as the polycomb repressive complex 2 (PRC2), resulting in the deposition of H3K27me3 and repression of critical genes involved in apoptosis and cell cycle control (Gequelin et al., 2011; Cao et al., 2021; Scott, 2017). In epithelial cancers, EBV was shown to upregulate KDM5B—a histone demethylase—through EBNA1 and BZLF1, contributing to the silencing of PLK2 and activation of the PI3K/AKT/mTOR pathway, as demonstrated in EBV-associated NPC and EBVaGC models (Zhou et al., 2025).

EBV also encodes microRNAs, particularly from the BART and BHRF1 clusters, which function as epigenetic regulators. These miRNAs modulate viral and host gene expression by targeting transcripts such as BIM, PUMA, DICER1, and LMP1 itself, thereby influencing cell survival and immune evasion (Yau et al., 2014). EBV miRNAs can also downregulate host tumor suppressor miRNAs like the Let-7 family, contributing further to epigenetic dysregulation (Yau et al., 2014).

EBV-mediated epigenetic reprogramming extends to permanent changes in host chromatin. EBV infection of epithelial cells (e.g., nasopharyngeal and gastric) results in long-lasting epigenetic alterations, even after loss of the viral genome. Studies using telomerase-immortalized oral keratinocytes and gastric epithelial models showed that EBV induces CIMP, delays differentiation, enhances invasiveness, and alters gene expression in ways that mimic cancer phenotypes (Yau et al., 2014; Scott, 2017).

The epigenetic profiles of EBV-associated cancers vary by tissue type. In BL, EBV-positive tumors show widespread DNA hypermethylation and lower mutational burden than their EBV-negative counterparts, suggesting that EBV epigenetic modulation may replace the need for genetic mutations (Scott, 2017). In HL, EBV induces a hypomethylation phenotype in germinal center B cells through differential expression of DNMT isoforms, contributing to the phenotype of Reed–Sternberg cells (Cao et al., 2021). In EBVaGC, EBV induces hypermethylation of critical tumor suppressor genes including p16, APC, and PTEN—hallmarks of this gastric cancer subtype (Yau et al., 2014).

Because EBV-induced epigenetic modifications are reversible, they represent attractive therapeutic targets. DNA methyltransferase inhibitors (e.g., decitabine, azacitidine) and histone deacetylase inhibitors (e.g., vorinostat, romidepsin) have shown efficacy in preclinical models of EBV-associated malignancies (Mabe et al., 2024; Ocaña-Paredes et al., 2024). Furthermore, inhibition of KDM5B with AS-8351 suppressed tumor growth in NPC xenografts, reinforcing the potential of targeting EBV-activated histone demethylases (Zhou et al., 2025).

One of the most extensively characterized epigenetic alterations in HBV-related HCC is the hypermethylation of CpG islands in tumor suppressor gene promoters, including p16, RASSF1A, E-cadherin, and GSTP1. HBx enhances the expression of DNA methyltransferases (DNMT1, DNMT3A, DNMT3B), promoting transcriptional silencing of these genes (Tian and Ou, 2015; Dandri, 2020). This process not only favors malignant transformation but also contributes to the maintenance of viral persistence by silencing immune regulatory genes (Farazi and DePinho, 2006).

HBx also disrupts histone post-translational modifications by recruiting or modulating histone-modifying enzymes, such as HDACs and histone methyltransferases. These interactions result in histone deacetylation or methylation at specific loci, leading to chromatin condensation and gene repression. For example, histone H3K9 and H3K27 trimethylation, linked to gene silencing, are enriched in HBx-expressing cells (Yang et al., 2022; Zhang et al., 2024b).

HBV, particularly through HBx, alters the expression of miRNAs and lncRNAs, which serve as key regulators of gene expression. Several miRNAs downregulated by HBx (e.g., miR-122, miR-199a-3p) target oncogenes and signaling pathways such as Wnt/β-catenin, PI3K/AKT, and TGF-β, while others promote angiogenesis and epithelial–mesenchymal transition (EMT) (Levrero and Zucman-Rossi, 2016; Tian et al., 2013). Concurrently, dysregulated lncRNAs like HULC and HEIH act as competing endogenous RNAs, sponging tumor-suppressive miRNAs and driving HCC progression (Yang et al., 2022).

The viral covalently closed circular DNA (cccDNA) acts as a stable minichromosome within hepatocytes. HBx modulates the epigenetic status of cccDNA by recruiting histone acetyltransferases and methyltransferases, thereby regulating viral gene expression and latency. These modifications allow HBV to persist despite antiviral treatment and contribute to treatment resistance (Yang et al., 2022; Dandri, 2020).

Chronic HBV infection alters the epigenetic landscape of immune cells, impairing antiviral responses. HBx induces immunosuppressive environments through epigenetic reprogramming of cytokine genes and immune checkpoint molecules, enabling viral persistence and fostering a pro-tumorigenic inflammatory microenvironment (Levrero and Zucman-Rossi, 2016; Zhang et al., 2024b).

Targeting HBV-driven epigenetic alterations offers promising avenues for therapy. Agents such as DNMT inhibitors (e.g., azacytidine, decitabine) and HDAC inhibitors (e.g., entinostat, panobinostat) are being investigated for their capacity to reverse gene silencing and sensitize HCC cells to chemotherapy and immunotherapy (Lin et al., 2025; Tian et al., 2013). Moreover, modulation of non-coding RNAs and inhibition of epigenetic regulators affecting cccDNA may provide new strategies for viral clearance and HCC prevention (Dandri, 2020; Yang et al., 2022). Lastly, HBV promotes hepatocarcinogenesis through multilayered epigenetic modifications. HBx-mediated dysregulation of DNA methylation, histone modification, and non-coding RNA expression profoundly alters both viral and host gene networks. These insights underscore the significance of epigenetic therapies in managing HBV-associated liver cancer and emphasize the need for further mechanistic and translational research.

HCV-associated HCC can arise even after viral clearance through direct-acting antivirals (DAAs), suggesting that infection leaves a durable epigenetic “scar” on hepatocytes. These alterations include long-lasting changes in histone marks (e.g., H3K27ac and H3K9me3), chromatin accessibility, and DNA methylation that dysregulate key cancer-related pathways such as Wnt/β-catenin and TGF-β signaling (García-Crespo et al., 2023; Hamdane et al., 2019). Genome-wide studies have shown that these HCV-induced epigenetic marks persist in patients with sustained virological response (SVR), potentially contributing to post-SVR HCC risk (Hamdane et al., 2019; Lohmann and Bartenschlager, 2019).

Chronic HCV infection leads to both global hypomethylation and regional hypermethylation in promoter CpG islands. Tumor suppressor genes including RASSF1A, SOCS1, and CDKN2A are frequently silenced through DNA hypermethylation, while global hypomethylation contributes to genomic instability and aberrant gene expression (Zhao et al., 2021; Dash et al., 2020). These methylation patterns can be detected in circulating cell-free DNA, highlighting their potential as non-invasive biomarkers (Braghini et al., 2022; Pan et al., 2024).

HCV core and non-structural proteins (particularly NS5A) interact with chromatin modifiers such as HDACs and methyltransferases to alter histone marks. These changes can suppress immune-related genes and promote oncogene expression, establishing a pro-carcinogenic chromatin environment even in the absence of active viral replication (Zhao et al., 2021; Dash et al., 2020; Hamdane et al., 2019).

miRNAs and lncRNAs are significantly dysregulated in HCV-infected livers. For example, downregulation of tumor-suppressive miR-122 and upregulation of oncogenic lncRNAs such as HOTAIR and HULC are common in HCV-related HCC (Pan et al., 2024; Feng, 2013). These non-coding RNAs influence epigenetic machinery by targeting DNMTs, HDACs, and polycomb repressive complexes, reinforcing transcriptional silencing of tumor suppressors and enhancing EMT and stemness features (Feng, 2013; Braghini et al., 2022).

HCV-driven epigenetic changes promote a cancer stem cell–like phenotype by activating stemness pathways (Wnt, Notch, Hedgehog) and repressing differentiation-related genes. Epigenetic reprogramming facilitates EMT, enhancing invasiveness and metastatic potential (Pan et al., 2024; Zhao et al., 2021). Polycomb group proteins (e.g., EZH2) and histone demethylases are implicated in this transformation and are considered actionable targets (García-Crespo et al., 2023; Feng, 2013).

While DAA therapy achieves high SVR rates and reduces liver inflammation, recent studies reveal that epigenetic alterations established during chronic infection may not be reversed upon viral clearance. This may explain the persistent risk of HCC after SVR, especially in patients with advanced fibrosis or cirrhosis (Dash et al., 2020; Hamdane et al., 2019; Fiehn et al., 2024). Thus, understanding the durability and functional consequences of HCV-induced epigenetic changes is essential for post-therapy surveillance and risk stratification (Hamdane et al., 2019; Lohmann and Bartenschlager, 2019).

Epigenetic biomarkers are being investigated for early detection of HCV-related HCC, including methylated DNA loci and non-coding RNAs detectable in serum (Pan et al., 2024). Lastly, epigenetic drugs such as DNMT inhibitors (e.g., azacytidine) and HDAC inhibitors (e.g., vorinostat) are being explored for their capacity to reverse epigenetic silencing and restore immune responsiveness (Braghini et al., 2022; Zhao et al., 2021).

Tax plays a central role in ATL pathogenesis by modulating chromatin structure. It recruits histone-modifying enzymes and transcriptional coactivators to key gene loci. For example, Tax activates NF-κB signaling through KDR-dependent stabilization, which promotes chromatin remodeling and survival of infected T cells (Mohanty et al., 2024). Tax also upregulates histone methyltransferases like EZH2 and DNMT3B, leading to aberrant accumulation of H3K27me3 and hypermethylation of CpG islands at tumor suppressor loci including CDKN2A, TP53, and SOCS1 ( Yamagishi et al., 2021 ; Rosewick et al., 2017 ; Matsuo et al., 2022 ). These modifications silence genes critical for cell cycle regulation and apoptosis. Furthermore, integrative genomic studies have shown that Tax disrupts global chromatin accessibility patterns, establishing repressive chromatin at differentiation genes and open chromatin at oncogenic enhancers (Lieberman, 2016). A novel enhancer within the HTLV-1 provirus itself has been identified as a regulatory hotspot driving persistent antisense transcription, further supporting the epigenetic basis of viral latency and transformation (Matsuo et al., 2022).

A key discovery in HTLV-1 epigenetic oncogenesis is the remodeling of super-enhancers at transcription factor hubs. The HTLV-1-encoded HBZ protein binds a super-enhancer within the BATF3 locus, amplifying a transcriptional program driven by BATF3 and IRF4—two master regulators of ATL proliferation. Disruption of this circuitry with BET inhibitors collapses the transcriptional network and suppresses ATL in preclinical models, highlighting its therapeutic relevance (Nakagawa et al., 2018).

HTLV-1 also reprograms the expression of non-coding RNAs. miR-31 and other tumor-suppressive microRNAs are downregulated through promoter hypermethylation, while oncogenic lncRNAs like HOTAIR and ANRIL are upregulated, contributing to immune evasion and proliferative advantage (Yamagishi et al., 2019; Xiao et al., 2025). These epigenetic changes in non-coding RNA expression further reinforce the leukemic phenotype.

A major breakthrough in HTLV-1-related cancer therapy is the development of valemetostat, a dual EZH1/2 inhibitor. Valemetostat has demonstrated durable clinical responses in ATL by eliminating H3K27me3-enriched chromatin and reactivating silenced tumor suppressor genes (Yamagishi et al., 2024). Single-cell epigenomic analyses revealed that resistance emerges through compensatory DNA methylation mediated by elevated DNMT3A or TET2 mutations, underscoring the complexity of chromatin homeostasis in therapy resistance (Yamagishi et al., 2024). BET inhibitors, which disrupt enhancer function and transcription factor recruitment, have also shown efficacy in ATL xenografts and ex vivo models (Nakagawa et al., 2018). Their combination with HDACis is being explored to enhance therapeutic response and overcome resistance mechanisms (Yamagishi et al., 2024, Yamagishi et al., 2019). HTLV-1 drives ATL through multilayered epigenetic mechanisms including aberrant DNA methylation, histone modification, enhancer hijacking, and non-coding RNA deregulation. These changes are orchestrated primarily by the viral proteins Tax and HBZ and converge on the silencing of tumor suppressors and the amplification of oncogenic transcriptional programs. The approval and clinical success of epigenetic modulators such as valemetostat mark a turning point in ATL management and open the door to rational combination therapies targeting chromatin dynamics and transcriptional addiction in HTLV-1-induced malignancies (Mohanty et al., 2024; Fujikawa et al., 2016).

Lastly, the virus-specific epigenetic mechanisms of HPV, EBV, HBV, HCV, and HTLV-1 is summarized in Table 1 .

Immunotherapies have emerged as powerful tools to treat virus-associated malignancies. Unlike conventional therapies, immune-based approaches can specifically distinguish infected from non-infected cells. Strategies include the adoptive transfer of virus-specific T cells (VSTs), checkpoint blockade, and dendritic cell (DC)-based vaccines. Clinical trials using EBV- and HPV-targeted T cells have shown durable responses in nasopharyngeal carcinoma, EBV-positive lymphomas, and cervical cancer (Tashiro and Brenner, 2017; Chakravorty et al., 2022). Moreover, adoptive cell therapies (ACTs) targeting virally encoded tumor antigens like EBNA1 (EBV), E6/E7 (HPV), HBx (HBV), and Tax (HTLV-1) are under exploration (Zhang et al., 2024a). In HTLV-1, Tax remains a key therapeutic target due to its role in maintaining leukemic cell survival through NF-κB activation and immune escape (Mohanty et al., 2024).

Despite the availability of prophylactic vaccines for HPV and HBV, therapeutic vaccines aimed at eliciting robust cytotoxic T cell responses are under active investigation. However, their effectiveness is often dampened by the immunosuppressive tumor microenvironment. To overcome this, combination regimens involving therapeutic vaccines and metronomic chemotherapy—low-dose, frequent chemotherapeutic schedules—have been shown to enhance immunogenicity in HPV- and EBV-driven tumors (Zhang et al., 2024a; Faghihkhorasani et al., 2023; Kyriakidis et al., 2021; Ortiz-Prado et al., 2021). Additionally, oncolytic virotherapy represents a dual-function platform capable of lysing tumor cells while stimulating antiviral immunity ( Figure 2 ). Herpesviruses and adenoviruses engineered to express immune stimulators are being explored in EBV- and HPV-positive tumors (Faghihkhorasani et al., 2023). In the case of HTLV-1, early-phase studies of peptide-based Tax vaccines and DC-Tax immunotherapy show potential to induce antitumor responses and reduce viral load in ATL patients, although clinical efficacy remains to be fully validated (Rosewick et al., 2017; Xiao et al., 2025).

The unique biology of virus-induced cancers has driven efforts to repurpose non-cancer drugs (e.g., antivirals, anti-inflammatories) with known safety profiles. Metformin, statins, and NSAIDs have demonstrated anti-proliferative effects in HPV- and HBV-associated cancers through both metabolic and epigenetic reprogramming (Fernandes, 2024; Chowdhary et al., 2023; López-Cortés et al., 2021). In ATL, studies suggest that repurposed drugs that target NF-κB signaling or autophagy pathways—such as KDR inhibitors—may impair Tax stability and HTLV-1 cell survival (Mohanty et al., 2024). These drugs are being evaluated in combination with epigenetic therapies or immune checkpoint inhibitors to overcome resistance and improve outcomes (Fernandes, 2024; Chowdhary et al., 2023; Mohanty et al., 2024; Nakagawa et al., 2018).

Current antiviral therapies effectively suppress viral replication (e.g., nucleos(t)ide analogs for HBV, direct-acting antivirals for HCV), but do not eliminate latent infections or reverse virus-induced epigenetic changes. In this context, epigenetic drugs such as DNMTis (e.g., azacitidine) and HDACis (e.g., vorinostat) are being evaluated for their ability to reactivate silenced immune genes and sensitize virus-driven tumors to immunotherapy (Ahmed and Jha, 2023; Wang et al., 2018; Chowdhary et al., 2023). Targeting viral miRNAs and host epigenetic regulators also holds promise for disrupting immune evasion strategies, particularly in EBV-driven cancers (Zhang et al., 2024a). In HTLV-1-associated ATL, the dual EZH1/2 inhibitor valemetostat has shown promising clinical activity, reversing H3K27me3-mediated silencing and restoring expression of pro-apoptotic and cell cycle regulators. Valemetostat was recently approved in Japan for relapsed/refractory ATL (Yamagishi et al., 2024). Additionally, BET inhibitors targeting BRD4-mediated transcriptional addiction in HTLV-1-transformed cells have shown preclinical efficacy and are being considered for combination strategies with HDACis or immunomodulators (Nakagawa et al., 2018; Matsuo et al., 2022).

Advances in omics and systems pharmacology are enabling the identification of virus-specific molecular signatures and actionable targets. In HPV-associated cancers, integrated transcriptomic and metabolomic analyses have identified natural compounds and phytochemicals capable of reversing E6/E7-induced immune evasion (Aarthy et al., 2022). Similarly, in HTLV-1, epigenomic profiling has uncovered enhancer landscapes and non-coding RNA networks (e.g., miR-31, HOTAIR, ANRIL) that may serve as predictive biomarkers or therapeutic targets (Xiao et al., 2025; Yamagishi et al., 2019). Single-cell ATAC-seq and methylome studies in ATL are aiding in stratifying patients by their epigenetic vulnerability to EZH2 or BET inhibition (Yamagishi et al., 2021, Yamagishi et al., 2024).