Conventional chemotherapeutics may induce immunogenic cancer cell death or stimulate immune effectors via so-called off-target effects. The study by Besch et al. in this issue of the JCI now demonstrates that agents designed to stimulate the innate immune system by activating intracellular pattern recognition receptors can kill cancer cells in a direct, cell-autonomous fashion (see the related article beginning on page 2399). The authors show that ligation of viral RNA sensors, such as RIG-I or MDA-5, by viral RNA mimetics triggers mitochondrial apoptosis in human melanoma cells in an IFN-independent fashion. The data suggest that tumor cell killing and immunostimulation may synergize for optimal anticancer immunochemotherapy.