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Rather than acting through isolated pathways, viral oncoproteins systematically rewire host regulatory networks, rendering conventional single\u2010target oncology paradigms vulnerable to rapid resistance and clinical failure. Systems pharmacology offers a transformative, network\u2010centric framework that views virus\u2010driven cancers as systemic perturbations of host protein\u2010protein interaction networks. This review synthesises computational methodology, network topology, and drug discovery strategies across major human oncoviruses. We examine how graph centrality algorithms, quantitative network proximity metrics (Z\u2010score), and complementary exposure synergy modelling (S\n                    <jats:sub>AB<\/jats:sub>\n                    ) uncover hidden network vulnerabilities and guide targeted drug repurposing. Despite distinct genomic structures and tissue tropisms, oncogenic viruses converge on shared host interactome hubs, notably TP53, AKT1, BCL2, MYC, STAT3, and VEGFA, to drive cell cycle dysregulation, apoptotic suppression, and microenvironmental remodelling. We evaluate repositioned synthetic pharmaceuticals (such as kinase inhibitors and host ion channel blockers) and multi\u2010target bioactive formulations, detailing their mechanisms in targeting viral host dependencies. Finally, we address key translational bottlenecks, including disparities between in silico binding predictions and in vivo pharmacokinetics, extensive plasma protein binding, tumour penetration barriers, and viral latency reservoirs. Overcoming these hurdles will require integrating deep graph learning, single\u2010cell spatial multi\u2010omics, and patient\u2010derived organoid models to accelerate the clinical realization of network\u2010targeted therapies in viral oncology.\n                  <\/jats:p>","DOI":"10.1002\/rmv.70201","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:06:55Z","timestamp":1792062415000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systems Pharmacology of Human Oncoviruses: Network\u2010Based Drug Discovery for Virus\u2010Driven Cancers"],"prefix":"10.1002","volume":"36","author":[{"given":"Jingyi","family":"Sun","sequence":"first","affiliation":[{"name":"School of Biomedical and Chemical Engineering Liaoning Institute of Science and Technology  Benxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changning","family":"Song","sequence":"additional","affiliation":[{"name":"School of Biomedical and Chemical Engineering Liaoning Institute of Science and Technology  Benxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Hua","sequence":"additional","affiliation":[{"name":"School of Biomedical and Chemical Engineering Liaoning Institute of Science and Technology  Benxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Pang","sequence":"additional","affiliation":[{"name":"School of Biomedical and Chemical Engineering Liaoning Institute of Science and Technology  Benxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4809-739X","authenticated-orcid":false,"given":"Shuaiting","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Biomedical and Chemical Engineering Liaoning Institute of Science and Technology  Benxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology14070797"},{"key":"e_1_2_16_3_1","first-page":"1","volume-title":"Viruses and Human Cancer: From Basic Science to Clinical Prevention","author":"Schiller J. 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