ISG15 depletion enhances oHSV-1 replication and antitumor efficacy in oral squamous cell carcinoma

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.