Активация белка ZBP1 может превращать «холодные» опухоли в мишени для иммунотерапии

A new Review published in the open-access journal Ferroptosis and Oxidative Stress highlights Z-nucleic acid-binding protein 1 (ZBP1) as an emerging innate immune sensor that converts genomic stress into potent antitumor immunity. The authors propose that therapeutic activation of the ZBP1 pathway may transform immunologically "cold" tumors into "hot" tumors, offering new opportunities to overcome resistance to cancer immunotherapy. In the article, "ZBP1-mediated sensing of genomic stress in cancer therapy," Dr. Xiao Zhong, Professor Siddharth Balachandran, Professor Ting Zhang, provide a comprehensive overview of the rapidly evolving biology of ZBP1 and its emerging role in cancer therapy. Originally recognized as an antiviral receptor, ZBP1 is now understood to function as a sensor of genomic and transcriptomic instability by recognizing Z-DNA and Z-RNA structures generated during endogenous retroelement activation, splicing stress, R-loop formation, viral mimicry, and other forms of cellular stress. The Review synthesizes recent discoveries linking genomic stress sensing to regulated cell death and antitumor immune activation. Cancer therapies increasingly exploit genomic stress to eliminate tumor cells. However, many tumors remain resistant because they fail to generate sufficient immune activation following treatment. The authors describe how ZBP1 serves as a critical molecular checkpoint that detects stress-associated nucleic acids and initiates necroptosis, a highly inflammatory form of regulated cell death capable of stimulating robust antitumor immune responses. Rather than simply killing cancer cells, ZBP1-mediated necroptosis promotes the release of tumor antigens and damage-associated molecular patterns (DAMPs), creating conditions that enhance immune surveillance. The Review further explores the intimate relationship between ZBP1 signaling and oxidative stress. Upon activation, ZBP1 engages the RIPK1–RIPK3–MLKL signaling axis to trigger necroptosis, while reactive oxygen species (ROS) both promote pathway activation and are further amplified during necroptotic cell death. This feed-forward interaction positions oxidative stress as both a regulator and an amplifier of ZBP1-mediated immune signaling, strengthening the link between redox biology and cancer immunotherapy. One of the central themes of the Review is the therapeutic potential of combining viral mimicry strategies with ZBP1 activation. Treatments such as epigenetic modulators, curaxins, and splicing inhibitors can induce the accumulation of endogenous Z-form nucleic acids, thereby activating ZBP1. When coupled with localized ROS-generating approaches or nanomedicine platforms, these strategies may selectively induce immunogenic necroptosis within tumors. The resulting inflammatory response can recruit dendritic cells, enhance CD8⁺ T-cell infiltration, and improve the efficacy of immune checkpoint blockade by converting poorly infiltrated "cold" tumors into immune-responsive "hot" tumors. Beyond summarizing current mechanistic advances, the authors discuss key challenges that must be addressed before ZBP1-directed therapies can be translated into clinical practice. These include identifying biomarkers to stratify patients according to ZBP1 pathway activity, optimizing combination treatment strategies, understanding tumor-specific regulation of necroptosis, and minimizing unwanted inflammatory toxicity. Integrating genomic stress induction, redox modulation, and precision nanomedicine may ultimately maximize the therapeutic potential of the ZBP1 pathway. By reframing ZBP1 as more than an antiviral sensor, this Review positions genomic stress sensing as a central regulator of immunogenic cell death and antitumor immunity. The authors suggest that targeting the ZBP1–RIPK3–MLKL axis may represent a promising strategy for overcoming therapeutic resistance and expanding the clinical benefits of cancer immunotherapy, opening a new frontier at the intersection of innate immunity, oxidative stress, and regulated cell death.