Graphical Abstract Highlights d 5-AZA-CdR induces formation of dsRNAs and activation of the MDA5/MAVS/IRF7 pathway d An anti-proliferative response to DNA demethylation is mediated by viral mimicry d 5-AZA-CdR-mediated targeting of CICs is mainly mediated by viral mimicry d The MDA5/MAVS/IRF7 pathway is a potentially druggable target against colorectal cancer In Brief Anti-tumor DNA-demethylating agents act by inducing transcription of endogenous dsRNAs that activate the viral recognition and interferon response pathway. This anti-viral response reduces proliferation of colorectal cancer-initiating cells. Accession Numbers GSE62086 Roulois et al., 2015, Cell 162, 961–973 August 27, 2015 ª2015 Elsevier Inc.
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