Abstract
Virus-infected cells release type 1 interferons, which induce an antiviral state in neighboring cells. Naturally occurring viruses are therefore equipped with stealth replication strategies to limit virus sensing and/or with combat strategies to prevent or reverse the antiviral state. Here we show that oncolytic viruses with simple RNA genomes whose spread was suppressed in tumor cells pretreated with interferon were able to replicate efficiently when the cells were coinfected with a poxvirus known to encode a diversity of innate immune combat proteins. In vivo the poxvirus was shown to reverse the intratumoral antiviral state, rescuing RNA virus replication in an otherwise restrictive syngeneic mouse tumor model leading to antitumor efficacy. Pairing of complementary oncolytic viruses is a promising strategy to enhance the antitumor activity of this novel class of anticancer drugs.