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

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Solid tumors are often "cold" and resistant to treatment, necessitating strategies to induce immunogenic cell death (ICD).
• Z-DNA binding protein 1 (ZBP1) functions as a key sensor that translates cellular nucleic acid stress into ICD.
• ZBP1 acts as a central hub, integrating various nucleic acid stress signals to initiate cell death pathways.

Purpose of the Study:

• To review ZBP1's role in linking diverse nucleic acid stress signals to PANoptosis.
• To explore therapeutic strategies that leverage ZBP1 activation for cancer treatment.
• To propose a roadmap for translating ZBP1-targeting therapies into clinical practice.

Main Methods:

• Literature review of ZBP1's function in nucleic acid sensing and cell death.
• Analysis of emerging therapeutic approaches targeting ZBP1.
• Discussion of translational strategies, including combination therapies and biomarkers.

Main Results:

• ZBP1 integrates signals from DNA damage, telomere crisis, replication stress, RNA splicing, retroelements, and mitochondrial stress.
• Various therapeutic strategies, including biological agents and small molecules, can engage ZBP1.
• Targeting ZBP1 holds potential for inducing antitumor immunity.

Conclusions:

• ZBP1 is a critical mediator of ICD and PANoptosis in response to nucleic acid stress.
• Targeting the ZBP1 signaling axis presents a viable therapeutic avenue for "cold" tumors.
• Biomarker-guided combination strategies are essential for effective clinical translation.