{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T11:28:56Z","timestamp":1788607736938,"version":"build-2803163510"},"reference-count":86,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Oncolytic viruses represent an emerging class of therapeutic agents that have the potential to transform the care of patients with melanoma. In this narrative review, we describe the evolution of oncolytic virus approaches. We begin by describing early investigations using wild type viruses and then the development of sophisticated Herpes simplex virus 1 (HSV-1) variant constructs such as talimogene laherparepvec (T-VEC) and vusolimogene oderparepvec (Replimune-1, RP1), which incorporate deletions of viral genes and expression of human or synthetic transgenes to promote tumor selectivity, dendritic cell recruitment, antigen presentation, and stimulation of systemic anti-tumor immune responses. We review the status of clinical trials of oncolytic viruses in melanoma, highlight regulatory challenges, and describe important concepts and key remaining questions within the field. While T-VEC remains the only Food and Drug Administration (FDA)-approved oncolytic virus for melanoma treatment, ongoing research focusing on next-generation viral constructs and combination strategies aims to further improve clinical outcomes and expand the applicability of oncolytic virus therapy in melanoma.<\/jats:p>","DOI":"10.3390\/cells14201620","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T10:28:36Z","timestamp":1760696916000},"page":"1620","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Evolution, Current Landscape, and Future Prospects of Oncolytic Virotherapy in Melanoma: Talimogene Laherparepvec and Beyond"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7922-3319","authenticated-orcid":false,"given":"John","family":"Smestad","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA"},{"name":"Physician-Scientist Training Program, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4883-5301","authenticated-orcid":false,"given":"John","family":"Rieth","sequence":"additional","affiliation":[{"name":"Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Laux","sequence":"additional","affiliation":[{"name":"Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Milhem","sequence":"additional","affiliation":[{"name":"Holden Comprehensive Cancer Center, University of Iowa Health Care, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1097\/00000441-190412740-00001","article-title":"The Influence of Complicating Diseases Upon Leukaemia","volume":"127","author":"Dock","year":"1904","journal-title":"Am. 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