Epstein‐Barr Virus MicroRNAs as Key Regulators of Lymphoma Pathogenesis: Immune Evasion Mechanisms and Therapeutic Opportunities

ABSTRACT

The ubiquitous human gamma‐herpesvirus Epstein–Barr virus (EBV) infects over 90% of adults globally and was the first human virus identified with oncogenic potential. EBV enters a lifelong persistence in the host via a finely regulated life‐cycle comprising primary infection, latency and lytic reactivation. Within infected B‐cells and epithelial cells, EBV encodes a distinct repertoire of microRNAs (miRNAs), primarily from the BART (BamHI A rightward transcript) and BHRF1 (BamHI H rightward open reading frame) clusters, which play pivotal roles in modulating both viral and host gene expression. These viral miRNAs contribute to key oncogenic processes: by dampening apoptotic responses (e.g., via targeting PUMA, Bim, and PTEN), promoting proliferation of latently‐infected B‐cells, inhibiting host immune responses (e.g., via down‐regulation of CXCL‐11 by miR‐BHRF1‐3), and promoting epithelial‐mesenchymal transition (EMT) and metastasis through modulation of E‐cadherin and other adhesion molecules. In human lymphomas, such as Burkitt lymphoma, Hodgkin lymphoma, and EBV‐positive diffuse large B‐cell lymphoma, the interplay of latent viral gene expression, miRNA‐mediated regulatory networks, and host microenvironmental factors underlies malignant transformation and disease progression. Emerging evidence also supports the utility of EBV‐encoded miRNAs as diagnostic and prognostic biomarkers in EBV‐associated cancers. Importantly, therapeutic strategies aimed at interrupting viral miRNA function, restoring host tumor‐suppressor pathways, and re‐sensitizing tumor cells to immune surveillance hold promise. This review synthesizes current mechanistic insights into EBV‐encoded miRNAs in oncogenesis, elaborates on their roles in lymphoma pathogenesis, and evaluates the translational potential of miRNA‐targeted therapies in EBV‐associated malignancies.