DNA methylation dysregulation in EBV-associated lymphoproliferative disorders: molecular mechanisms and therapeutic advances

Epstein-Barr virus–associated lymphoproliferative disorders (EBV-LPDs) are a heterogeneous group of diseases in which aberrant DNA methylation interacts with EBV infection, host genetic mutations, metabolic reprogramming, and immune dysregulation. The purpose of this review is to systematically synthesize current evidence on DNA methylation dysregulation across diverse EBV-LPDs and explore its therapeutic implications, providing a comprehensive overview of the epigenetic mechanisms underlying these disorders. A key feature of EBV-LPDs is the bidirectional interplay between EBV infection and DNA methylation networks: EBV actively remodels both viral and host epigenomes to facilitate latency maintenance and immune evasion, thereby promoting disease progression. Therapeutically, hypomethylating agents have demonstrated clinical activity in selected lymphoma cohorts and can directly remodel the EBV epigenome in vivo. However, most combination trials have not prospectively stratified patients by EBV status. The “epigenetic priming” strategy—using transient epigenetic reprogramming before sequential chemotherapy, immunotherapy, or cellular therapy—is supported by growing preclinical and clinical evidence, although its EBV-specific therapeutic benefit remains to be established. Aberrant DNA methylation contributes to the pathobiology of several EBV-LPDs and represents a potentially actionable therapeutic vulnerability in selected subtypes. However, the absence of standardized epigenetic biomarkers and prospective stratification by EBV status remain major translational barriers. Future studies should prioritize biomarker-guided epigenetic strategies, prospective EBV-status assessment, and preclinical validation of emerging approaches such as CRISPR/dCas9 epigenome editing.