ADAR and Immune Silencing in Cancer.

The regulation of immune responses by tumors is central to their survival. By diminishing the production of interferon (IFN) and other inflammatory mediators, tumors enhance immune evasion. Responses initiated by nucleic acid sensors and triggered by dysregulated RNA transcription and cytoplasmic DNA undergo down-modulation in tumors. A protein hub that involves the double-stranded RNA (dsRNA) editing enzyme adenosine deaminase RNA specific (ADAR), the RNase DICER1, and the dsRNA-activated kinase protein activator of PKR (PACT) mediates many of these tumor-intrinsic responses, with in vitro ADAR dependency varying by tumor type (range 11-80%). The central role played by ADAR, both as an enzyme and as a scaffold, sets it as a target for cancer immunotherapy. Therapeutic approaches focusing on the ADAR p150 isoform and its Z-DNA- and Z-RNA-specific Zα domain find support from recent mouse and human studies.