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Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity

Jun Xie,Shaowei Wang,Yunhong Zhong,Ming Gao,Xuezhang Tian,Liting Zhang,Dongli Pan,Qingsong Qin,Bing Wu,Ke Lan,Zhi-Jun Sun,Junjie Zhang

Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo . Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy.