Scientists have found a compound that helped a tumor-targeting virus kill liver cancer more effectively while sparing healthy cells, which could someday translate to a viable treatment approach in humans. Viruses that selectively kill cancer cells (dubbed oncolytic viruses) have, so far, delivered disappointingly limited therapeutic benefits in human trials, despite promising preclinical studies. Seeking a means to boost the antitumor effects of the oncolytic virus M1, Haipeng Zhang and colleagues screened 350 small molecules to identify compounds that enhanced viral killing of cultured hepatocellular carcinoma (HCC) cells. HCC is the second leading cause of cancer-related death in men, claiming more than 700,000 lives per year worldwide. M1 is a mosquito-borne pathogen that predominantly causes mild illness in horses, but selectively kills HCC cells due to cancer-intrinsic deficiencies in antiviral defense. Combining M1 with Eeyarestatin I (an inhibitor of the protein VCP, which has been linked to causing malignancy) increased the potency of the oncolytic virus by as much as 3,600-fold against six lines of HCC cells in culture, whereas the dual regimen had no effect on non-cancerous cells. In multiple mouse models of HCC (including non-immunodeficient animals), M1 together with Eeyarestatin I shrank tumors and prolonged survival compared to single treatments. The researchers further demonstrated that the duo was safe and well-tolerated in nonhuman primates. According to the authors, high VCP expression (which correlated with worse clinical outcomes) could zero in on patients who might benefit most from oncolytic virus combination therapy.