One of the mechanisms used by epigenetic therapy is the elevation of host cell-derived double stranded RNA (dsRNA) baseline levels through overexpression of genomic repetitive elements especially Alu retroelements. The dsRNAs trigger immunogenic responses since immune system cannot distinguish between endogenous and exogenous dsRNAs derived from viral infections; hence called “Viral mimicry response”. These dsRNAs are recognized by pattern recognition receptors (PRRs) such as MDA-5 which further induce inflammatory responses through interferon secretion. However, the response is limited through the function of some editing enzymes such as ADAR1 which destabilizes the formation of dsRNAs and renders the therapy less efficient through attenuating interferon secretion by immune cells. Since, some cancer cells can survive even after ADAR1 inhibition, it is speculated that there might be other mechanism which contribute to dsRNA destabilization. Since dsRNA formation derived from retroelement transcripts mimics viral infections, we tried to review the mechanistic approaches applied during host-pathogen interaction to highlight a possible candidate which might be cogitable for further investigations in epigenetic therapy. dsRNAs produced by RNA viruses are sensed by PRRs and activate nuclear factor erythroid 2 p45-related factor 2 (NRF2) which further downregulates STING protein and attenuates IFN release. RNA viruses such as SARS-CoV-2 have the potential to impair NRF2 signaling and eliminate its inhibitory effect from STING, leading to excessive release of IFNs and destroy pulmonary cells through cytokine release storm (CRS). Here, we briefly explain that NRF2, in a very downstream side of anti-viral response, might be a potential candidate target in combination with epigenetic therapy to circumvent the limitations in cancer epigenetic therapy.

Epigenetic therapy, Viral mimicry, Interferon, Immunotherapy