{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:39:58Z","timestamp":1793039998921,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"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>High-grade gliomas\u2014particularly glioblastoma (GBM)\u2014remain refractory to standard-of-care surgery followed by chemoradiation, with a median overall survival of ~15 months. Oncolytic viruses (OVs), which selectively infect and lyse tumor cells while engaging antitumor immunity, offer a mechanistically distinct therapeutic modality. This review synthesizes clinical progress of OVs in GBM, with emphasis on oncolytic herpes simplex virus (oHSV) and coverage of other vectors (adenovirus, reovirus, Newcastle disease virus, vaccinia virus) across phase I\u2013III trials, focusing on efficacy and safety. Key observations include the encouraging clinical trajectory of oHSV exemplars\u2014T-VEC (approved for melanoma) and G47\u0394 (approved in Japan for recurrent GBM)\u2014the multi-center exploration of the adenovirus DNX-2401 combined with programmed death-1 (PD-1) blockade, and the early-stage status of reovirus (pelareorep) and Newcastle disease virus programs. Emerging evidence indicates that oHSV therapy augments immune infiltration within the tumor microenvironment and alleviates immunosuppression, with synergy when combined with chemotherapy or immune checkpoint inhibitors. Persistent challenges include GBM\u2019s inherently immunosuppressive milieu, limitations imposed by the blood\u2013brain barrier, intrapatient viral delivery and biodistribution, and concerns about viral shedding. Future directions encompass programmable vector design, optimization of systemic delivery, biomarker-guided patient selection, and rational combination immunotherapy. Collectively, OVs represent a promising immunotherapeutic strategy in GBM; further gains will hinge on vector engineering and precision combinations to translate mechanistic promise into durable clinical benefit.<\/jats:p>","DOI":"10.3390\/cancers17243948","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T16:11:18Z","timestamp":1765383078000},"page":"3948","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Oncolytic Viruses in Glioblastoma: Clinical Progress, Mechanistic Insights, and Future Therapeutic Directions"],"prefix":"10.3390","volume":"17","author":[{"given":"Jiayu","family":"Liu","sequence":"first","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Dang","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junru","family":"Hei","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanteng","family":"Li","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Gao","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjuan","family":"Bai","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenying","family":"Lv","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Senior Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100853, 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