Oncolytic virotherapy is rapidly progressing through clinical evaluation. However, the therapeutic efficacy of oncolytic viruses in humans has been less than expected from preclinical studies. We describe an anticancer drug screen for compounds that enhance M1 oncolytic virus activity in hepatocellular carcinoma (HCC). An inhibitor of the valosin-containing protein (VCP) was identified as the top sensitizer, selectively increasing potency of the oncolytic virus up to 3600-fold. Further investigation revealed that VCP inhibitors cooperated with M1 virus–suppressed inositol-requiring enzyme 1α (IRE1α)–X-box binding protein 1 (XBP1) pathway and triggered irresolvable endoplasmic reticulum (ER) stress, subsequently promoting robust apoptosis in HCC. We show that VCP inhibitor improved the oncolytic efficacy of M1 virus in several mouse models of HCC and primary HCC tissues. Finally, this combinatorial therapeutic strategy was well tolerated in nonhuman primates. Our study identifies combined VCP inhibition and oncolytic virus as a potential treatment for HCC and demonstrates promising therapeutic potential.

溶瘤病毒疗法正在通过临床评估迅速发展。然而，溶瘤病毒对人类的治疗功效低于临床前研究的预期。我们描述了在肝细胞癌（HCC）中增强M1溶瘤病毒活性的化合物的抗癌药物筛选。含缬草素的蛋白质（VCP）的抑制剂被确定为最强敏化剂，选择性地将溶瘤病毒的效力提高至3600倍。进一步的研究表明，VCP抑制剂与M1病毒抑制的肌醇需要酶1α（IRE1α）–X-box结合蛋白1（XBP1）途径协同作用，并触发了不可分辨的内质网（ER）应激，从而促进了HCC的强大凋亡。我们表明，VCP抑制剂在HCC和原发性HCC组织的几种小鼠模型中提高了M1病毒的溶瘤功效。最后，这种组合治疗策略在非人类灵长类动物中具有良好的耐受性。我们的研究确定了VCP抑制和溶瘤病毒的组合作为HCC的潜在治疗方法，并证明了有希望的治疗潜力。