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Oncolytic virotherapy demonstrates a promising strategy that combines direct tumor cell lysis with immune activation. Tumor-selective viruses replicate within malignant cells, induce cell death, and release tumor antigens, thereby reshaping the immunosuppressive microenvironment. Several viral backbones have advanced to clinical testing, including adenovirus (DNX-2401), herpes simplex virus (G47\u0394, G207), poliovirus (PVS-RIPO), measles virus (MV-CEA), reovirus (pelareorep), vaccinia virus (Pexa-Vec), and vesicular stomatitis virus (VSV-GP). The approval of G47\u0394 in Japan for malignant glioma marks a milestone, with early trials demonstrating safety and signals of durable benefit, particularly in combination regimens. Current research emphasizes engineering viral genomes to enhance selectivity, immune stimulation, and resistance to clearance, while exploring synergistic combinations with radiotherapy, chemotherapy, immune checkpoint inhibitors, and tumor-treating fields. Advances in delivery, such as convection-enhanced infusion and blood\u2013brain barrier modulation, are also under investigation. Despite obstacles, oncolytic virotherapy holds significant potential within multimodal GBM strategies.<\/jats:p>","DOI":"10.3390\/cancers17213465","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:02:01Z","timestamp":1761670921000},"page":"3465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Emerging Role of Oncolytic Virotherapy in Glioblastoma Management"],"prefix":"10.3390","volume":"17","author":[{"given":"Damir","family":"Nizamutdinov","sequence":"first","affiliation":[{"name":"Department of Neurosurgery and Neuroscience Institute, Baylor Scott & White Health, Temple, TX 76508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sentmanat","sequence":"additional","affiliation":[{"name":"College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2493-8760","authenticated-orcid":false,"given":"Xiaoming","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Baylor Scott & White Health, Temple, TX 76508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhong","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Neuroscience Institute, Baylor Scott & White Health, Temple, TX 76508, USA"},{"name":"Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou 215005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7015-1849","authenticated-orcid":false,"given":"Dan","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Neuroscience Institute, Baylor Scott & White Health, Temple, TX 76508, USA"},{"name":"Department of Neurosurgery, Baylor College of Medicine, Temple, TX 76508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1680-3639","authenticated-orcid":false,"given":"Erxi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Neuroscience Institute, Baylor Scott & White Health, Temple, TX 76508, USA"},{"name":"Department of Neurosurgery, Baylor College of Medicine, Temple, TX 76508, USA"},{"name":"Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX 77843, USA"},{"name":"LIVESTRONG Cancer Institutes, Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4426-0168","authenticated-orcid":false,"given":"Jason H.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery and Neuroscience Institute, Baylor Scott & White Health, Temple, TX 76508, USA"},{"name":"Department of Neurosurgery, Baylor College of Medicine, Temple, TX 76508, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iii1","DOI":"10.1093\/neuonc\/noab200","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014\u20132018","volume":"23","author":"Ostrom","year":"2021","journal-title":"Neuro Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105780","DOI":"10.1016\/j.phrs.2021.105780","article-title":"Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance","volume":"171","author":"Wu","year":"2021","journal-title":"Pharmacol. 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