ZBP1-mediated sensing of genomic stress in cancer therapy

Abstract

Z-nucleic acid-binding protein 1 (ZBP1) is a cytosolic innate immune sensor that detects left-handed Z-DNA and Z-RNA, structures arising from endogenous retroelements, splicing stress, R-loops, viruses, or viral mimicry. Originally viewed as an antiviral receptor, ZBP1 has emerged as a sentinel of genomic and transcriptomic instability. Upon ligand binding, ZBP1 recruits receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and receptor-interacting serine/threonine-protein kinase 3 (RIPK3) via RIP homotypic interaction motif domains; in humans, RIPK1 acts as an essential scaffold to form the necrosome, which phosphorylates mixed lineage kinase domain-like pseudokinase (MLKL) and triggers necroptosis, a lytic, immunogenic cell death. This pathway is intimately regulated by reactive oxygen species (ROS): oxidative stress promotes RIPK1 activation, and necroptosis further drives a mitochondrial ROS burst, establishing a feed-forward amplification loop. In cancer, therapeutic induction of viral mimicry (e.g., using curaxins or splicing inhibitors) combined with tumor-localized ROS generation activates ZBP1-driven necroptosis, leading to the release of damage-associated molecular patterns and tumor antigens. This process converts immunosuppressive “cold” tumors into inflamed “hot” tumors, enhancing dendritic cell maturation, CD8+ T cell infiltration, and sensitivity to immune checkpoint blockade. Integrating epigenetic priming, nanomedicine, and patient stratification according to ZBP1/RIPK3/MLKL pathway status holds promise for overcoming therapeutic resistance. Thus, ZBP1-mediated nucleic acid surveillance represents a central innate checkpoint bridging genomic stress to antitumor immunity.

Keywords

Necroptosis / Z-nucleic acid-binding protein 1 / Z-RNA / reactive oxygen species / viral mimicry

Acknowledgements

The authors declare that AI tools (ChatGPT-5.5 and Claude-4.5) were used solely for language polishing during the manuscript preparation process. The authors take full responsibility for the integrity, originality, and accuracy of the work.

Authors contribution

Zhang T: Conceptualization, methodology, supervision, writing-review & editing. Zhong X: Investigation, data curation, writing-original draft. Balachandran S: Supervision, writing-review & editing.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 32370157), 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University (Grant No. ZYYC24008), and Fundamental Research Funds for the Central Universities (Grant No. 20822041J4064).

Copyright

© The Author(s) 2026.

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