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Research Article

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

Valeriia Tsekhovska
1,2
Erica Diani
3
Noel Onyango
4,5
George Ichoho
4,5
Davide Gibellini
3
Pier Paolo Piccaluga
1,2*

1 Biobank of Research, IRCCS Azienda Ospedaliera-Universitaria di Bologna Policlinico di S. Orsola, Bologna

2 Department of Medical and Surgical Sciences, Bologna University School of Medicine, Bologna

3 Microbiology Unit, Department of Diagnostics and Public Health, University of Verona, Verona

4 Department of Microbiology and Immunology, University of Nairobi, Nairobi

5 KAVI-Institute for Clinical Research, University of Nairobi, Nairobi



Tumor Discovery 2026, 5(2),025260056; https://doi.org/10.36922/TD025260056
Submitted26 Jun 2025
Revised03 Nov 2025
Accepted04 Nov 2025
Published18 Nov 2025
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Cite This Article
Valeriia Tsekhovska ,Erica Diani ,Noel Onyango ,George Ichoho ,Davide Gibellini ,Pier Paolo Piccaluga . (2026). <p>Beyond Epstein&ndash;Barr virus: Unveiling the role of herpesviruses in lymphoma pathogenesis</p>. Tumor Discovery , 5(2), TD025260056. https://doi.org/10.36922/TD025260056
Abstract

Beyond the well-documented oncogenic role of Epstein–Barr virus (EBV), a growing body of evidence implicates other herpesviruses, notably Kaposi’s sarcoma-associated 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 non-EBV 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.

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