Engaging the ZBP1 axis: from nucleic acid stress to antitumor immunity

Most solid tumors remain immunologically 'cold' and refractory to therapy, making immunogenic cell death (ICD) induction a central therapeutic goal. Z-DNA binding protein 1 (ZBP1) acts as a sensor, converting intrinsic nucleic acid stress into ICD programs. This review establishes ZBP1 as a convergence point linking distinct nucleic acid stress signals, including DNA damage response, telomere crisis, replication stress, dysregulated RNA splicing, endogenous retroelement re-expression, and mitochondrial stress response, to PANoptosis. We highlight recent therapeutic strategies, ranging from biological inducers and direct agonists to Z-DNA proteolysis targeting chimeras and pharmacological stressors, that harness nucleic acid stress responses to engage ZBP1. Finally, we propose a translational roadmap emphasizing combination strategies and biomarker-guided patient selection to engage the ZBP1 signaling axis and promote durable antitumor immunity.