Cancer frenemy pathways: Inducing immunogenic cell death by exploiting apoptosis-interferon antagonism with oncolytic viruses

The term “frenemy,” a portmanteau of “friend” and “enemy,” describes a relationship that blends cooperation and antagonism, with overt collaboration often masking underlying tension.1 Analogously, many signaling pathways and biological programs that preserve tissue integrity in normal contexts assume ambivalent roles in cancer, simultaneously sustaining tumor survival while encoding vulnerabilities exploitable therapeutically. Within this framework, synthetic lethality, originally defined in classical genetics as a condition where combined disruption of two genes is lethal whereas perturbation of either alone is tolerated, has expanded from discrete gene pairs to encompass interactions among pathways, functional states, and higher-order processes.