Qiu Manman, Wei Rongrong, Zhang Qicheng, Zhao Jiawei, Zhang Hongkai, Tan Juan, Qiao Wentao
Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, PR China.
Virology. 2025 May;606:110504. doi: 10.1016/j.virol.2025.110504. Epub 2025 Mar 17.
Oncolytic viruses (OVs) represent a promising experimental therapy for a range of cancers, including oral squamous cell carcinoma (OSCC). In this study, oHSV refers to an oncolytic virus engineered from HSV-1(Herpes Simplex Virus Type 1). The oHSV-1 is an oncolytic virus derived from HSV-1, where both copies of the ICP34.5 coding sequences have been replaced with the EGFP gene, and the ICP47 gene has been deleted. In previous studies, resistance was observed in certain SCC15 xenograft models treated with oncolytic herpes simplex viruses (oHSV-1). Primary tumor cells were extracted from these resistant models, followed by RNA sequencing with SCC15 cells as controls. Analysis revealed that ISG15 expression was upregulated in the resistant primary cells, as well as in HSV-infected breast cancer cells (GSE137757). In this study, we confirmed that knockdown ISG15 in SCC15 cells enhanced oHSV-1 replication, while ISG15 overexpression suppressed it. Mechanistic studies demonstrated that ISG15 inhibits oHSV-1 replication via ISGylation. To improve the therapeutic efficacy of oHSV-1, an oHSV-1 variant expressing ISG15-targeting short hairpin RNA (shRNA), termed oHSV-1-shISG15, was engineered. oHSV-1-shISG15 exhibited enhanced antitumor efficacy compared to oHSV-1 in vitro and in vivo. These findings suggest that ISG15 depletion augments oHSV-1 replication in OSCC tumor cells through ISGylation inhibition. Meanwhile, this study provides a novel recombinant oncolytic virus to potentiate the efficacy of oncolytic herpes virotherapy.
溶瘤病毒（OVs）是一种针对包括口腔鳞状细胞癌（OSCC）在内的多种癌症极具前景的实验性疗法。在本研究中，oHSV指的是一种由单纯疱疹病毒1型（HSV-1）改造而来的溶瘤病毒。oHSV-1是一种源自HSV-1的溶瘤病毒，其ICP34.5编码序列的两个拷贝均已被EGFP基因取代，且ICP47基因已被删除。在先前的研究中，在用溶瘤单纯疱疹病毒（oHSV-1）治疗的某些SCC15异种移植模型中观察到了耐药性。从这些耐药模型中提取原发性肿瘤细胞，随后以SCC15细胞作为对照进行RNA测序。分析显示，耐药原发性细胞以及HSV感染的乳腺癌细胞（GSE137757）中ISG15表达上调。在本研究中，我们证实敲低SCC15细胞中的ISG15可增强oHSV-1复制，而ISG15过表达则抑制其复制。机制研究表明，ISG15通过ISGylation抑制oHSV-1复制。为提高oHSV-1的治疗效果，构建了一种表达靶向ISG15短发夹RNA（shRNA）的oHSV-1变体，称为oHSV-1-shISG15。与oHSV-1相比，oHSV-1-shISG15在体外和体内均表现出增强的抗肿瘤效果。这些发现表明，ISG15的缺失通过抑制ISGylation增强了oHSV-1在OSCC肿瘤细胞中的复制。同时，本研究提供了一种新型重组溶瘤病毒，以增强溶瘤疱疹病毒疗法的疗效。
