{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:55:17Z","timestamp":1792086917272,"version":"4.4.0"},"reference-count":133,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Classic Hodgkin lymphoma (cHL) in patients with immune deficiency\/dysregulation represents a critical unmet need in hematology, demanding the appropriate revision of classification and therapeutic paradigms. Epstein\u2013Barr virus (EBV) is a pivotal driver of lymphomagenesis in this high-risk subset, where viral oncoproteins (e.g., LMP1\/2A) exploit immune vulnerabilities to activate NF-\u03baB, rewire tumor microenvironments (TME), and evade immune surveillance. EBV-positive cHL, prevalent in immunosuppressed populations, exhibits distinct molecular hallmarks, including reduced somatic mutations, unique HLA associations, and profound PD-L1-mediated immune suppression, that diverge from EBV-negative cases reliant on genetic aberrations. Despite advances in combined antiretroviral therapy, HIV co-infection exacerbates pathogenesis, M2 macrophage dominance, and T-cell exhaustion, while links to other viruses remain ambiguous. Current therapies fail to adequately target these viral and immune complexities, leaving patients with poorer outcomes. This review synthesizes insights into EBV\u2019s etiological role, immune contexture disparities, and the genetic\u2013environmental interplay shaping cHL heterogeneity. The WHO classification highlights the need to reclassify EBV-associated cHL as a distinct subset, integrating viral status and immune biomarkers into diagnostic frameworks. Urgent priorities include global epidemiological studies to clarify causal mechanisms, development of virus-targeted therapies (e.g., EBV-specific T-cell strategies, PD-1\/CTLA-4 blockade), and personalized regimens for immune-dysregulated cohorts.<\/jats:p>","DOI":"10.3390\/cancers17091433","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T04:08:24Z","timestamp":1745554104000},"page":"1433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Immune Deficiency\/Dysregulation-Associated EBV-Positive Classic Hodgkin Lymphoma"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9390-5645","authenticated-orcid":false,"given":"Mohamed Nazem","family":"Alibrahim","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7226-1942","authenticated-orcid":false,"given":"Annunziata","family":"Gloghini","sequence":"additional","affiliation":[{"name":"Department of Avanced Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico IRCCS, Istituto Nazionale dei Tumori Milano, 20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-639X","authenticated-orcid":false,"given":"Antonino","family":"Carbone","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","unstructured":"Kaseb, H., and Babiker, H.M. 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