Accumulating evidence has shown that activation of RIG-I/MDA5 signaling in cancers cells by RNA ligands (5′ppp RNA or oncolytic viruses) induces cancer cell apoptosis in a type I IFN-dependent or -independent manner (Poeck et al., 2008; Besch et al., 2009; Chiappinelli et al., 2015; Roulois et al., 2015; Yu et al., 2016), while depletion of RIG-I in human tumors confers resistance to ionizing radiation and many chemotherapy drugs (Ranoa et al., 2016). The gene discussed is IFIH1; the disease is cancer.