In this study, we report a microenvironment-responsive virus-mimetic reactor (RVR) integrating adenosine deaminases acting on RNA 1 (ADAR1)-targeting DNAzymes (AD) and decitabine (DAC) to improve radiotherapy outcome, which could syncretically disrupt the repressive epigenetic machineries to drive necroptosis for inhibiting post-RT survival and promoting antitumor immune responses. Specifically, DAC promotes the transcription of retroelements into double-strand RNAs (dsRNAs) by inhibiting DNA methyltransferase (DNMT), while AD exerts viral nucleic acid-like recyclable reactivity to degrade ADAR1 mRNA to impair dsRNA clearance, which cooperatively activate Z DNA-binding protein 1 (ZBP1)-mixed lineage kinase domain like pseudokinase (MLKL) signaling to drive tumor cell necroptosis while inducing viral mimicry response for stimulating T cell-mediated immune responses. Furthermore, DAC-mediated DNA demethylation markedly upregulates major histocompatibility complex-1 (MHC-1) and co-stimulatory molecules to enhance the cytotoxic potential of activated CD8+ T cells. Combining radiotherapy and RVRs evokes potent viral infection-like tumoricidal and vaccination effects for effective systemic tumor eradication.
