ZBP1-Driven Necroptosis Potentiates Immunotherapy and Is Blocked by ADAR1

Reactivation of endogenous retroviral elements (ERE) has been shown to improve responses to immune checkpoint blockade (ICB) therapy. These EREs are unleashed when adenosine deaminase RNA specific 1 (ADAR1), which binds to ERE-derived double-stranded RNA (dsRNA), is ablated. These dsRNAs can adopt either the right-handed (A-RNA) or left-handed (Z-RNA) double-helical conformation. The ADAR1 p150 isoform has the ability to bind and quench Z-RNA, which are activating ligands for Z-form nucleic acid binding protein 1 (ZBP1), a cell death–initiating host sensor protein. To test if ADAR1 repression prevents endogenous Z-RNA production and blocks ZBP1-driven necroptosis, Zhang, Yin, Fedorov, and colleagues disrupted the Adar gene in mouse embryo fibroblasts (MEF) and showed that Z-RNAs spontaneously accumulated. Investigation into the Z-RNAs that are repressed by ADAR1 demonstrated that most are protein-coding mRNAs, many of which included IFN-stimulated genes hyper-edited in the 3’ untranslated region. Sequestration of these Z-RNAs by ADAR1 p150 was able to prevent activation of ZBP1, as wild-type MEFs (which express ZBP1) began dying after ADAR1 loss. As no ADAR1 inhibitors are currently available, a small-molecule screen was conducted to overcome the need for ADAR1 loss and identify compounds capable of directly generating Z-DNA (which are also ZBP1 ligands). The compound CBL0137 was identified as capable of inducing Z-DNA formation, and treatment of both MEFs and human fibroblasts with CBL0137 bypassed the need for ADAR1 ablation and induced ZBP1-dependent necroptosis. Furthermore, in models of malignant melanoma, dual treatment with CBL0137 and an anti–PD-1 antibody showed induction of necroptosis in fibroblasts in the tumor microenvironment, accompanied by dendritic cell and CD8⁺ T-cell recruitment into tumors. These T cells displayed markers of activation, proliferation, and effector function, resulting in potent regression of melanomas. Overall, this study shows that ADAR1 p150 prevents Z-RNA accumulation, and its loss can trigger ZBP1-dependent necroptosis. This can be induced by a small molecule currently in phase I clinical trials and be harnessed as an adjuvant to rekindle immunotherapy responsiveness of immunologically silenced tumors.

Zhang T, Yin C, Fedorov A, Qiao L, Bao H, Beknazarov N, et al. ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature 2022 May 25 [Epub ahead of print].

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