Fig. 4.

Depletion of ADAR1 induces vulnerability in cancer cells. RNA-editing efficiency and the expression of adenosine deaminase acting on RNA 1 (ADAR1) are generally upregulated in most cancers. Loss of RNA editing followed by ADAR1 depletion activates multiple double-stranded (ds)RNA-sensing pathways mediated by melanoma differentiation-associated protein 5 (MDA5), protein kinase R (PKR), and oligoadenylate synthetase (OAS), which produces 2′,5′-oligoadenylate (2-5A) resulting in activation of RNase L. The activation of these pathways leads to type I interferon (IFN) production and translational arrest, which make cancer cells vulnerable. In addition, ADAR1 depletion causes cancer cells to be more sensitive to cancer immunotherapy involving, for instance, anti–programmed cell death 1 (PD-1) antibodies