Molecular mechanisms of Epstein-Barr Virus in the pathogenesis of lymphomas and new opportunities for precision medicine.

Epstein-Barr Virus (EBV), a herpesvirus closely linked to multiple types of lymphoma, promotes tumorigenesis through various mechanisms, including inducing genomic instability, reprogramming key signaling pathways, and evading host immune surveillance. In Burkitt Lymphoma (BL), aberrant activation of the MYC gene is recognized as a pivotal driver event, while recent reports indicate that EBV nuclear antigen 1 (EBNA1) and latent membrane protein 1 (LMP1) significantly enhance tumor cell proliferation and immune evasion by regulating host chromatin structure and antigen presentation processes. In Diffuse Large B cell Lymphoma (DLBCL) and Hodgkin Lymphoma (HL), EBV latent proteins such as LMP1 and latent membrane protein 2A (LMP2A) activate the NF-κB and JAK/STAT signaling pathways, reshaping the tumor microenvironment, enhancing anti-apoptotic survival signals, and promoting immune suppression. Furthermore, EBV-encoded microRNAs and long non-coding RNAs (lncRNAs) further modulate host gene expression and metabolic pathways, increasing tumor heterogeneity and therapeutic resistance. Despite advances in targeting MYC, the PI3K/AKT pathway, and immune checkpoints, issues such as resistance, high toxicity, and the complexity of the tumor microenvironment limit their clinical applicability. Emerging immunotherapies, including CAR-T cell therapy, EBV-specific T-cell therapy, and epigenetic targeting, show significant potential in optimizing the immune microenvironment and overcoming therapeutic resistance. However, the molecular heterogeneity of EBV-associated lymphomas poses greater challenges for precision medicine strategies. Future research needs to integrate multi-omics data to elucidate the complex molecular interactions between EBV and its host, laying the groundwork for the development of multi-targeted combinatorial therapies and innovative diagnostic and therapeutic approaches. This review systematically summarizes the core mechanisms by which EBV contributes to lymphoma pathogenesis and evaluates the breakthroughs and challenges of current therapeutic strategies. It also outlines the future directions of precision medicine, based on multi-disciplinary integration, to enhance the understanding of the molecular pathology of EBV-associated lymphomas and optimize personalized treatment.