Immune checkpoint blockade (ICB) therapies represent a groundbreaking paradigm in cancer treatment, reshaping clinical approaches. Despite their efficacy, relapse remains a common challenge with poorly understood acquired resistance mechanisms. In this study, leveraging multiple mouse models of ICB relapse, we identify that the features of acquired resistance in cancer cells include: 1) heightened expression of resistance-associated interferon-stimulated genes (ISGs), 2) persistent virus mimicry linked to endogenous retroelement derepression, dsRNA accumulation, and heightened pattern recognition receptor (PRR) signaling, and 3) consequential epigenetic modifications in resistant tumor subclones. We demonstrate that subjecting cancer cells to chronic interferon (IFN) stimulation over 3-4 weeks instigates features associated with IFN-driven resistance, contingent upon the dsRNA PRR MDA5. Intriguingly, inhibition of IFN signaling through a JAKi/TBK1i combination for a comparable duration induces a reversal of these IFN resistance-associated characteristics. Our study identifies a mechanism wherein prolonged IFN exposure induces epigenetic alterations and sustained virus mimicry which in turn are required for the upregulation of resistance-associated ISGs, thus perpetuating acquired resistance to ICB. This work enhances our understanding of the evolution between the immune system and cancer cells during ICB therapies with implications for refining future ICB therapy combinations.