ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

Nature. 2022 Jun;606(7914):594-602. doi: 10.1038/s41586-022-04753-7. Epub 2022 May 25.


Only a small proportion of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy and prevents ICB responsiveness by repressing immunogenic double-stranded RNAs (dsRNAs), such as those arising from the dysregulated expression of endogenous retroviral elements (EREs)1-4. These dsRNAs trigger an interferon-dependent antitumour response by activating A-form dsRNA (A-RNA)-sensing proteins such as MDA-5 and PKR5. Here we show that ADAR1 also prevents the accrual of endogenous Z-form dsRNA elements (Z-RNAs), which were enriched in the 3' untranslated regions of interferon-stimulated mRNAs. Depletion or mutation of ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, which culminated in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumour immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily translatable avenue for rekindling the immune responsiveness of ICB-resistant human cancers.

MeSH terms

  • 3' Untranslated Regions
  • Adenosine Deaminase* / metabolism
  • Animals
  • Cancer-Associated Fibroblasts
  • Carbazoles / pharmacology
  • Humans
  • Immunotherapy / trends
  • Interferons / metabolism
  • Melanoma
  • Mice
  • Necroptosis*
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Neoplasms* / pathology
  • RNA, Double-Stranded / immunology
  • RNA-Binding Proteins* / metabolism


  • 3' Untranslated Regions
  • CBLC137
  • Carbazoles
  • RNA, Double-Stranded
  • RNA-Binding Proteins
  • ZBP1 protein, human
  • Zbp1 protein, mouse
  • Interferons
  • ADAR protein, human
  • ADAR1 protein, mouse
  • Adenosine Deaminase