Beyond Epstein–Barr virus: Unveiling the role of herpesviruses in lymphoma pathogenesis

Beyond the well-documented oncogenic role of Epstein–Barr virus (EBV), a growing body of evidence implicates other herpesviruses, notably Kaposi’s sarcomaassociated herpesvirus and human herpesvirus (HHV) 6, in the pathogenesis of specific lymphoma subtypes. HHV-7 has also been detected in lymphoma tissues, though its contribution remains less defined. This review systematically examines the epidemiological associations and experimental insights linking these nonEBV herpesviruses to lymphoid malignancies. The discussion delves into the molecular mechanisms through which virally encoded molecules influence critical cellular programs, including the modulation of immune responses, epigenetic reprogramming, and the induction of chronic inflammation. We also review how these viruses hijack multilayered cellular networks, such as nuclear factor kappa B and Janus Kinase/signal transducer and activator of transcription signaling, and reprogram cellular metabolism to support malignant growth. A critical re-evaluation of the evidence for HHV-7 positions it as a putative cofactor in lymphomagenesis, contingent on host immunosuppression, rather than a primary oncogenic driver, highlighting the current absence of proven causality and robust in vivo models. Furthermore, this review provides a structured overview of the clinical implications of these viral associations. We also outline the established diagnostic tools, such as immunohistochemistry and quantitative protein-coupled receptor (PCR), and emerging technologies such as droplet digital PCR and liquid biopsy that hold considerable promise to refine disease monitoring. Meanwhile, we delineate standard-of-care treatments for virus-associated lymphomas from promising investigational approaches, including virus-targeted interventions and novel immunotherapies, offering a framework for both current clinical practice and future research.