Inducing immunogenic cell death in tumors holds promise in stimulating anti-tumor immunity.A recent study published in Nature reported that a small molecule previously shown to induce the formation of Z-DNA activates ZBP1-dependent cell death and renders tumors sensitive to immune checkpoint blockade-based immunotherapy. Cancer immunotherapy by immune checkpoint blockade(ICB)has achieved remarkable success in individual cases;however,these are still restricted to a small number of patients.Therefore,novel approaches to enhance anti-tumor immunity are urgently needed.Induction of immunogenic cell death,such as necropto-sis,in tumor cells was shown to synergize with ICB to induce anti-tumor immune responses in mouse models.1 The RNA-editing enzyme adenosine deaminase acting on RNA 1(ADAR1)has emerged as a novel checkpoint conferring resistance to ICB therapy.2 ADAR1 catalyzes adenosine-to-inosine(A-to-I)editing in RNA,which prevents the formation of long double-stranded RNA(dsRNA)that activates the cytosolic RNA sensor melanoma differentiation-associated protein 5(MDA5)inducing type Ⅰ interferon(IFN)responses.The IFN-inducible ADAR1p150 isoform possesses a Zα domain that recognizes nucleic acids with a left-handed double helix structure,termed Z-nucleic acids(Z-NAs),including Z-RNA and Z-DNA.The only other protein in mammals known to harbor Zα domains is the IFN-inducible protein Z-DNA-binding protein 1(ZBP1),which has emerged as a Z-NA sensor inducing cell death,anti-viral immunity and inflammation.3 This raises the possibility that ADAR1p150 might inhibit ZBP1-mediated cell death by repressing the accumulation of Z-NAs,a mechanism potentially contributing to ICB therapy resistance.

Huipeng Jiao;Manolis Pasparakis

Institute for Genetics,University of Cologne,Cologne,Germany;Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases(CECAD),University of Cologne,Cologne,Germany;Center for Molecular Medicine(CMMC),University of Cologne,Cologne,Germany

细胞研究（英文版）

[1]Huipeng Jiao;Manolis Pasparakis-.Inducing Z-DNA overcomes immune checkpoint blockade resistance)[J].细胞研究（英文版）,2022(10):871-872

ZBP1, Cancer,necropto,ADAR1p150

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