In a study exploring the relationship between ADAR1 and ZBP1 in cancer, Zhang et al. described a small molecule, the curaxin CBL0137, which triggered Z-DNA formation in fibroblasts of TME to efficiently activate ZBP1-dependent nuclear necroptosis and strongly reversed immune checkpoint blockade (ICB) unresponsiveness in mouse models of melanoma. Here, ZBP1 is linked to cancer.