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Inhibition of VCP sensitizes hepatocellular carcinoma cells to oncolytic virus M1–induced apoptosis. A virus and its reinforcement Oncolytic viruses can be effective against a variety of cancers, including hepatocellular carcinoma, where a viral treatment is showing evidence of efficacy in people. Zhang et al. performed a high-throughput drug screen to search for compounds to pair with an oncolytic virus called M1 to further increase its effectiveness against hepatocellular carcinoma. Through this screen, they identified inhibitors of valosin-containing protein, then used them together with M1, and demonstrated the efficacy of this regimen in mouse models of cancer. In addition, the combination was well tolerated in primates, suggesting that the drug and virus combination may translate to human patients. 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.