Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis

Abstract Features of the cancer epigenome distinguish cancers from their respective cell of origin and establish therapeutic vulnerabilities that can be exploited through pharmacologic inhibition of DNA- or histone-modifying enzymes. Epigenetic therapies converge with cancer immunotherapies through “viral mimicry,” a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons. This review describes the initial characterization and expansion of viral mimicry–inducing approaches as well as features that “prime” cancers for viral mimicry induction. Increased understanding of viral mimicry in therapeutic contexts suggests potential physiologic roles in cellular homeostasis. Significance: Recent literature establishes elevated cytosolic double strand RNA (dsRNA) levels as a cancer-specific therapeutic vulnerability that can be elevated by viral mimicry–inducing therapies beyond tolerable thresholds to induce antiviral signaling and increase dependence on dsRNA stress responses mediated by ADAR1. Improved understanding of viral mimicry signaling and tolerance mechanisms reveals synergistic treatment combinations with epigenetic therapies that include inhibition of BCL2, ADAR1, and immune checkpoint blockade. Further characterization of viral mimicry tolerance may identify contexts that maximize efficacy of conventional cancer therapies.