{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:38:40Z","timestamp":1779914320868,"version":"3.53.1"},"reference-count":114,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:00:00Z","timestamp":1624320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.<\/jats:p>","DOI":"10.3390\/v13071200","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T22:10:59Z","timestamp":1624399859000},"page":"1200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment"],"prefix":"10.3390","volume":"13","author":[{"given":"Ifeanyi Kingsley","family":"Uche","sequence":"first","affiliation":[{"name":"Division of Biotechnology and Molecular Medicine, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin G.","family":"Kousoulas","sequence":"additional","affiliation":[{"name":"Division of Biotechnology and Molecular Medicine, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J. F.","family":"Rider","sequence":"additional","affiliation":[{"name":"Division of Biotechnology and Molecular Medicine, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ctrv.2018.02.004","article-title":"Targeting the microenvironment in solid tumors","volume":"65","author":"Belli","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the crime: Functions of cells recruited to the tumor microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41571-019-0218-0","article-title":"Adverse effects of immune-checkpoint inhibitors: Epidemiology, management and surveillance","volume":"16","author":"Martins","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41571-019-0297-y","article-title":"Engineering strategies to overcome the current roadblocks in CAR T cell therapy","volume":"17","author":"Rafiq","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/cgt.2015.11","article-title":"Oncolytic viruses: Focusing on the tumor microenvironment","volume":"22","author":"Kaufman","year":"2015","journal-title":"Cancer Gene Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1002\/ijc.32325","article-title":"Oncolytic virotherapy enhances the efficacy of a cancer vaccine by modulating the tumor microenvironment","volume":"145","author":"Koske","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3389\/fonc.2014.00074","article-title":"Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity","volume":"4","author":"Guo","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.cell.2017.08.027","article-title":"Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy","volume":"170","author":"Ribas","year":"2017","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nrd4663","article-title":"Oncolytic viruses: A new class of immunotherapy drugs","volume":"14","author":"Kaufman","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/sj.cgt.7700537","article-title":"Oncolytic herpes simplex virus vectors for cancer virotherapy","volume":"9","author":"Varghese","year":"2002","journal-title":"Cancer Gene Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/sj.mt.6300108","article-title":"History of oncolytic viruses: Genesis to genetic engineering","volume":"15","author":"Kelly","year":"2007","journal-title":"Mol. Ther."},{"key":"ref_12","first-page":"473","article-title":"Studies in Hodgkin\u2019s syndrome; the association of viral hepatitis and Hodgkin\u2019s disease; a preliminary report","volume":"9","author":"Hoster","year":"1949","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1126\/science.1851332","article-title":"Experimental therapy of human glioma by means of a genetically engineered virus mutant","volume":"252","author":"Martuza","year":"1991","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/sj.cgt.7700771","article-title":"Replication-selective oncolytic viruses in the treatment of cancer","volume":"12","author":"Everts","year":"2005","journal-title":"Cancer Gene Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1200\/JCO.2014.58.3377","article-title":"Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma","volume":"33","author":"Andtbacka","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/sj.gt.3301885","article-title":"ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties","volume":"10","author":"Liu","year":"2003","journal-title":"Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.trecan.2017.09.006","article-title":"Migrating into the Tumor: A Roadmap for T Cells","volume":"3","author":"Gorris","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1126\/science.1129139","article-title":"Type, density, and location of immune cells within human colorectal tumors predict clinical outcome","volume":"313","author":"Galon","year":"2006","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/s41573-018-0007-y","article-title":"Approaches to treat immune hot, altered and cold tumours with combination immunotherapies","volume":"18","author":"Galon","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1073\/pnas.1904022116","article-title":"Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer","volume":"117","author":"Newman","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.trecan.2020.02.022","article-title":"Turning Cold into Hot: Firing up the Tumor Microenvironment","volume":"6","author":"Duan","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: The cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ma, W., He, H., and Wang, H. (2018). Oncolytic herpes simplex virus and immunotherapy. BMC Immunol., 19.","DOI":"10.1186\/s12865-018-0281-9"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Uche, I.K., Fowlkes, N., Vu, L., Watanabe, T., Carossino, M., Nabi, R., Del Piero, F., Rudd, J.S., Kousoulas, K.G., and Rider, P.J.F. (2021). Novel Oncolytic Herpes Simplex Virus 1 VC2 Promotes Long-Lasting, Systemic Anti-melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16F10-Derived Mouse Melanoma Model. J. Virol., 95.","DOI":"10.1128\/JVI.01359-20"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wirsching, H.G., Zhang, H., Szulzewsky, F., Arora, S., Grandi, P., Cimino, P.J., Amankulor, N., Campbell, J.S., McFerrin, L., and Pattwell, S.S. (2019). Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma. JCI Insight, 4.","DOI":"10.1172\/jci.insight.128217"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1038\/s41388-019-0737-2","article-title":"Eradication of glioblastoma by immuno-virotherapy with a retargeted oncolytic HSV in a preclinical model","volume":"38","author":"Alessandrini","year":"2019","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5006","DOI":"10.1038\/s41467-018-07344-1","article-title":"PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance","volume":"9","author":"Russell","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Leoni, V., Vannini, A., Gatta, V., Rambaldi, J., Sanapo, M., Barboni, C., Zaghini, A., Nanni, P., Lollini, P.L., and Casiraghi, C. (2018). A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007209"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1099\/0022-1317-75-12-3679","article-title":"ICP34.5 influences herpes simplex virus type 1 maturation and egress from infected cells in vitro","volume":"75 Pt 12","author":"Brown","year":"1994","journal-title":"J. Gen. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1126\/science.2173860","article-title":"Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture","volume":"250","author":"Chou","year":"1990","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1073\/pnas.94.3.843","article-title":"The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase","volume":"94","author":"He","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1084\/jem.187.3.341","article-title":"Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response","volume":"187","author":"Goldsmith","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.1128\/JVI.73.4.3375-3385.1999","article-title":"A herpesvirus ribosome-associated, RNA-binding protein confers a growth advantage upon mutants deficient in a GADD34-related function","volume":"73","author":"Mulvey","year":"1999","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6190","DOI":"10.1158\/1078-0432.CCR-17-0681","article-title":"Local Delivery of OncoVEX(mGM-CSF) Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade","volume":"23","author":"Moesta","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1245\/s10434-009-0809-6","article-title":"Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma","volume":"17","author":"Kaufman","year":"2010","journal-title":"Ann. Surg. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/nm0995-938","article-title":"Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas","volume":"1","author":"Mineta","year":"1995","journal-title":"Nat. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1128\/jvi.62.1.196-205.1988","article-title":"Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: Isolation and characterization of an ICP6 lacZ insertion mutant","volume":"62","author":"Goldstein","year":"1988","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1089\/10430349950018832","article-title":"Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity","volume":"10","author":"Toda","year":"1999","journal-title":"Hum. Gene Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1593\/neo.04265","article-title":"Multimutated herpes simplex virus g207 is a potent inhibitor of angiogenesis","volume":"6","author":"Cinatl","year":"2004","journal-title":"Neoplasia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/gt.2009.130","article-title":"Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment","volume":"17","author":"Huszthy","year":"2010","journal-title":"Gene Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/mt.2008.228","article-title":"Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM","volume":"17","author":"Markert","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1089\/hum.2020.101","article-title":"Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic HSV G207 to Treat Malignant Pediatric Cerebellar Brain Tumors","volume":"31","author":"Bernstock","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Friedman, G.K., Johnston, J.M., Bag, A.K., Bernstock, J.D., Li, R., Aban, I., Kachurak, K., Nan, L., Kang, K.D., and Totsch, S. (2021). Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas. N. Engl. J. Med.","DOI":"10.1056\/NEJMoa2024947"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1093\/neuonc\/now038","article-title":"Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: A report of the Children\u2019s Oncology Group ACNS0423 study","volume":"18","author":"Jakacki","year":"2016","journal-title":"Neuro Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s11060-017-2701-8","article-title":"Survival outcomes in pediatric recurrent high-grade glioma: Results of a 20-year systematic review and meta-analysis","volume":"137","author":"Kline","year":"2018","journal-title":"J. Neurooncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1099\/0022-1317-73-4-971","article-title":"Status of the ICP34.5 gene in herpes simplex virus type 1 strain 17","volume":"73 Pt 4","author":"Dolan","year":"1992","journal-title":"J. Gen. Virol."},{"key":"ref_48","first-page":"5714","article-title":"Role of the immune response during neuro-attenuated herpes simplex virus-mediated tumor destruction in a murine intracranial melanoma model","volume":"60","author":"Miller","year":"2000","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S1525-0016(03)00236-3","article-title":"HSV-1 therapy of primary tumors reduces the number of metastases in an immune-competent model of metastatic breast cancer","volume":"8","author":"Thomas","year":"2003","journal-title":"Mol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1038\/s41598-017-02503-8","article-title":"Cooperation of Oncolytic Herpes Virotherapy and PD-1 Blockade in Murine Rhabdomyosarcoma Models","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.ymthe.2005.03.026","article-title":"HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer","volume":"12","author":"Benencia","year":"2005","journal-title":"Mol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Kwan, A., Winder, N., Atkinson, E., Al-Janabi, H., Allen, R.J., Hughes, R., Moamin, M., Louie, R., Evans, D., and Hutchinson, M. (2020). Macrophages Mediate the Antitumor Effects of the Oncolytic Virus HSV1716 in Mammary Tumors. Mol. Cancer Ther.","DOI":"10.1158\/1535-7163.MCT-20-0748"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S0140-6736(00)04048-4","article-title":"Intralesional injection of herpes simplex virus 1716 in metastatic melanoma","volume":"357","author":"MacKie","year":"2001","journal-title":"Lancet"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3566","DOI":"10.1158\/1078-0432.CCR-16-2900","article-title":"Intratumoral Injection of HSV1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients","volume":"23","author":"Streby","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1016\/j.ymthe.2019.08.020","article-title":"First-in-Human Intravenous Seprehvir in Young Cancer Patients: A Phase 1 Clinical Trial","volume":"27","author":"Streby","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.lungcan.2020.10.007","article-title":"Oncolytic herpesvirus therapy for mesothelioma\u2014A phase I\/IIa trial of intrapleural administration of HSV1716","volume":"150","author":"Danson","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3389\/fonc.2017.00149","article-title":"Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials","volume":"7","author":"Eissa","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41417-019-0129-3","article-title":"Oncolytic activity of HF10 in head and neck squamous cell carcinomas","volume":"27","author":"Esaki","year":"2020","journal-title":"Cancer Gene Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jdermsci.2007.12.001","article-title":"Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10","volume":"50","author":"Watanabe","year":"2008","journal-title":"J. Dermatol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Hirooka, Y., Kasuya, H., Ishikawa, T., Kawashima, H., Ohno, E., Villalobos, I.B., Naoe, Y., Ichinose, T., Koyama, N., and Tanaka, M. (2018). A Phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4453-z"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1093\/annonc\/mdh225","article-title":"Intratumoral injection of herpes simplex virus HF10 in recurrent breast cancer","volume":"15","author":"Nakao","year":"2004","journal-title":"Ann. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1245\/ASO.2006.08.035","article-title":"Pilot study of oncolytic viral therapy using mutant herpes simplex virus (HF10) against recurrent metastatic breast cancer","volume":"13","author":"Kimata","year":"2006","journal-title":"Ann. Surg. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1080\/00016480600702100","article-title":"Intratumoral injection of herpes simplex virus HF10 in recurrent head and neck squamous cell carcinoma","volume":"126","author":"Fujimoto","year":"2006","journal-title":"Acta Otolaryngol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/cgt.2010.65","article-title":"A phase I dose-escalation clinical trial of intraoperative direct intratumoral injection of HF10 oncolytic virus in non-resectable patients with advanced pancreatic cancer","volume":"18","author":"Nakao","year":"2011","journal-title":"Cancer Gene Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1093\/infdis\/158.3.602","article-title":"In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020: Construction and evaluation in rodents","volume":"158","author":"Meignier","year":"1988","journal-title":"J. Infect. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1517\/13543784.17.7.1105","article-title":"Herpes simplex virus NV1020 as a novel and promising therapy for hepatic malignancy","volume":"17","author":"Kelly","year":"2008","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/sj.cgt.7700510","article-title":"Comparison of safety, delivery, and efficacy of two oncolytic herpes viruses (G207 and NV1020) for peritoneal cancer","volume":"9","author":"Bennett","year":"2002","journal-title":"Cancer Gene Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/S1091-255X(00)80106-7","article-title":"Effective treatment of pancreatic tumors with two multimutated herpes simplex oncolytic viruses","volume":"4","author":"McAuliffe","year":"2000","journal-title":"J. Gastrointest Surg."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1067\/mtc.2002.122297","article-title":"Replication-competent herpes virus NV1020 as direct treatment of pleural cancer in a rat model","volume":"124","author":"Ebright","year":"2002","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1096\/fj.00-0533fje","article-title":"Intravesical oncolytic viral therapy using attenuated, replication-competent herpes simplex viruses G207 and Nv1020 is effective in the treatment of bladder cancer in an orthotopic syngeneic model","volume":"15","author":"Cozzi","year":"2001","journal-title":"FASEB J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/S1072-7515(01)00866-3","article-title":"Effective treatment of head and neck squamous cell carcinoma by an oncolytic herpes simplex virus","volume":"193","author":"Wong","year":"2001","journal-title":"J. Am. Coll. Surg."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1089\/hum.2006.17.1214","article-title":"Phase I, open-label, dose-escalating study of a genetically engineered herpes simplex virus, NV1020, in subjects with metastatic colorectal carcinoma to the liver","volume":"17","author":"Kemeny","year":"2006","journal-title":"Hum. Gene Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1089\/hum.2010.020","article-title":"Phase I\/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver","volume":"21","author":"Geevarghese","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.immuni.2013.07.005","article-title":"Deciphering and reversing tumor immune suppression","volume":"39","author":"Motz","year":"2013","journal-title":"Immunity"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1089\/hum.2005.16.765","article-title":"Oncolytic HSV exerts direct antiangiogenic activity in ovarian carcinoma","volume":"16","author":"Benencia","year":"2005","journal-title":"Hum. Gene Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/mt.2009.232","article-title":"Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1","volume":"18","author":"Hardcastle","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/ijc.27681","article-title":"An armed oncolytic herpes simplex virus expressing thrombospondin-1 has an enhanced in vivo antitumor effect against human gastric cancer","volume":"132","author":"Tsuji","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1038\/mt.2008.112","article-title":"Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61","volume":"16","author":"Kurozumi","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-06-3145","article-title":"Angiogenic response caused by oncolytic herpes simplex virus-induced reduced thrombospondin expression can be prevented by specific viral mutations or by administering a thrombospondin-derived peptide","volume":"67","author":"Aghi","year":"2007","journal-title":"Cancer Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3389\/fmolb.2019.00160","article-title":"Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy","volume":"6","author":"Henke","year":"2019","journal-title":"Front. Mol. Biosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"513","DOI":"10.3389\/fimmu.2020.00513","article-title":"Virus-Induced T Cell-Mediated Heterologous Immunity and Vaccine Development","volume":"11","author":"Balz","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Xu, B., Ma, R., Russell, L., Yoo, J.Y., Han, J., Cui, H., Yi, P., Zhang, J., Nakashima, H., and Dai, H. (2018). An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma. Nat. Biotechnol.","DOI":"10.1038\/nbt.4302"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1158\/1078-0432.CCR-10-2213","article-title":"Chondroitinase ABC I-mediated enhancement of oncolytic virus spread and antitumor efficacy","volume":"17","author":"Dmitrieva","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1158\/0008-5472.CAN-05-2242","article-title":"Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector","volume":"66","author":"McKee","year":"2006","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1158\/0008-5472.CAN-07-2734","article-title":"Tissue inhibitor of metalloproteinase-3 via oncolytic herpesvirus inhibits tumor growth and vascular progenitors","volume":"68","author":"Mahller","year":"2008","journal-title":"Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Everts, A., Bergeman, M., McFadden, G., and Kemp, V. (2020). Simultaneous Tumor and Stroma Targeting by Oncolytic Viruses. Biomedicines, 8.","DOI":"10.3390\/biomedicines8110474"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1742-4658.2010.07919.x","article-title":"Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting","volume":"278","author":"Gialeli","year":"2011","journal-title":"FEBS J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.omto.2019.10.005","article-title":"GBM-Targeted oHSV Armed with Matrix Metalloproteinase 9 Enhances Anti-tumor Activity and Animal Survival","volume":"15","author":"Sette","year":"2019","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1038\/onc.2011.18","article-title":"TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells","volume":"30","author":"Anania","year":"2011","journal-title":"Oncogene"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/cgt.2012.70","article-title":"Tissue inhibitor of metalloproteinases-3 transfer suppresses malignant behaviors of colorectal cancer cells","volume":"19","author":"Lin","year":"2012","journal-title":"Cancer Gene Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4736","DOI":"10.1158\/0008-5472.CAN-07-6612","article-title":"Tissue inhibitor of metalloproteinase 3 suppresses tumor angiogenesis in matrix metalloproteinase 2-down-regulated lung cancer","volume":"68","author":"Chetty","year":"2008","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/sj.gt.3302717","article-title":"Development of a rapid method to generate multiple oncolytic HSV vectors and their in vivo evaluation using syngeneic mouse tumor models","volume":"13","author":"Terada","year":"2006","journal-title":"Gene Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"6850","DOI":"10.1158\/0008-5472.CAN-05-0154","article-title":"Brain tumor oncolysis with replication-conditional herpes simplex virus type 1 expressing the prodrug-activating genes, CYP2B1 and secreted human intestinal carboxylesterase, in combination with cyclophosphamide and irinotecan","volume":"65","author":"Tyminski","year":"2005","journal-title":"Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1099\/0022-1317-72-3-631","article-title":"Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in Glasgow strain 17+ between immediate early gene 1 and the \u2018a\u2019 sequence","volume":"72 Pt 3","author":"MacLean","year":"1991","journal-title":"J. Gen. Virol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"12006","DOI":"10.1073\/pnas.1307935110","article-title":"Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model","volume":"110","author":"Cheema","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1189\/jlb.1212621","article-title":"At the bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy","volume":"94","author":"Intlekofer","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"PD-1 and its ligands in tolerance and immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1111\/j.1600-065X.2008.00662.x","article-title":"Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways","volume":"224","author":"Fife","year":"2008","journal-title":"Immunol. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.immuni.2016.05.001","article-title":"Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation","volume":"44","author":"Anderson","year":"2016","journal-title":"Immunity"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1093\/annonc\/mdx686","article-title":"Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy","volume":"29","author":"Rotte","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.ccell.2017.07.006","article-title":"Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade","volume":"32","author":"Saha","year":"2017","journal-title":"Cancer Cell."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1200\/JCO.2017.73.7379","article-title":"Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma","volume":"36","author":"Chesney","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13027-018-0218-1","article-title":"Perspectives on immunotherapy via oncolytic viruses","volume":"14","author":"Reale","year":"2019","journal-title":"Infect. Agent Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1158\/0008-5472.CAN-17-0599","article-title":"Oncolytic Virotherapy Blockade by Microglia and Macrophages Requires STAT1\/3","volume":"78","author":"Delwar","year":"2018","journal-title":"Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Nair, M., Khosla, M., Otani, Y., Yeh, M., Park, F., Shimizu, T., Kang, J.M., Bolyard, C., Yu, J.G., and Kumar Banasavadi-Siddegowda, Y. (2020). Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation. Cancers, 12.","DOI":"10.3390\/cancers12041040"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"10153","DOI":"10.1128\/JVI.01133-08","article-title":"Construction of a fully retargeted herpes simplex virus 1 recombinant capable of entering cells solely via human epidermal growth factor receptor 2","volume":"82","author":"Menotti","year":"2008","journal-title":"J. Virol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1097\/00000658-200210000-00013","article-title":"Regulation of herpes simplex virus 1 replication using tumor-associated promoters","volume":"236","author":"Mullen","year":"2002","journal-title":"Ann. Surg."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/mt.2010.26","article-title":"Transcriptional and translational dual-regulated oncolytic herpes simplex virus type 1 for targeting prostate tumors","volume":"18","author":"Lee","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/mt.2014.177","article-title":"Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV","volume":"23","author":"Mazzacurati","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1128\/JVI.02468-15","article-title":"Deletion of a Predicted beta-Sheet Domain within the Amino Terminus of Herpes Simplex Virus Glycoprotein K Conserved among Alphaherpesviruses Prevents Virus Entry into Neuronal Axons","volume":"90","author":"Jambunathan","year":"2015","journal-title":"J. Virol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41577-018-0014-6","article-title":"Integrating oncolytic viruses in combination cancer immunotherapy","volume":"18","author":"Bommareddy","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s40425-018-0458-z","article-title":"Oncolytic virus immunotherapy: Future prospects for oncology","volume":"6","author":"Raja","year":"2018","journal-title":"J. Immuno. Cancer"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.ymthe.2017.03.026","article-title":"Oncolytic Virotherapy: A Contest between Apples and Oranges","volume":"25","author":"Russell","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_114","first-page":"47","article-title":"Cell carriers for oncolytic viruses: Current challenges and future directions","volume":"2","author":"Roy","year":"2013","journal-title":"Oncolytic Virotherapy"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1200\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:21:28Z","timestamp":1760163688000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,22]]},"references-count":114,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["v13071200"],"URL":"https:\/\/doi.org\/10.3390\/v13071200","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,22]]}}}