Abstract
Immune checkpoint inhibitors (ICIs) have transformed cancer care, yet durable responses remain limited in a majority of patients. This is particularly true of immunologically cold tumors, which are characterized by insufficient T-cell infiltration, low antigenicity, impaired adjuvanticity, and an immunosuppressive tumor microenvironment (TME). Z-form Nucleic Acid (Z-NA) Binding protein 1 (ZBP1)-initiated signaling, by overcoming these barriers, offers a mechanistic solution to rekindling ICI responsiveness in cold tumors. ZBP1 is an immune sensor which detects viral or endogenous Z-NAs, binds the kinase RIPK3, and activates Mixed Lineage Kinase Like pseudokinase (MLKL)-mediated necroptosis. ZBP1-initiated signaling can also inflame tumors non-cytolytically, including by activating inflammatory gene expression. Tumors frequently inactivate ZBP1 signaling, most notably by epigenetically silencing RIPK3. However, TME cells, particularly inflammatory cancer-associated fibroblasts (iCAFs), retain RIPK3 competence and represent a readily exploitable therapeutic vulnerability for activation of ZBP1-mediated immunogenic signaling within the tumor mass. Here, we discuss emerging strategies to activate ZBP1 within cold tumors as a means to enhance ICI-driven anti-tumor responses.
Introduction
Despite the revolutionary impact of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) pathways, durable responses from ICI monotherapy remain restricted to a minority of patients, with overall response rates of only 15%–40% across most solid tumors (Robert et al., 2015; ; Pilard et al., 2021; ). A reason for these underwhelming outcomes is that ICIs primarily function by releasing inhibitory checkpoints, or ‘immune brakes’, on pre-existing tumor-reactive T cells, rather than by initiating or orchestrating de novo anti-tumor immunity. Consequently, their efficacy is contingent upon a pre-existing functionally competent immune contexture which is frequently absent in immunologically cold tumors.
Immunologically cold tumors arise because cancers must avoid immune surveillance during oncogenesis (Mittal et al., 2014). They do so by disabling the antigen processing and presentation machinery (e.g., via loss of β2-microglobulin expression or downregulation of histocompatibility antigens), impairing interferon (IFN)-γ signaling, losing expression of target antigens, limiting T-cell recognition, and blunting cytotoxic T-cell activity (Galassi et al., 2024). However, these cell-intrinsic immune evasion strategies are only part of the problem. Cold tumors, particularly those with immune-desert and immune-excluded phenotypes, fail to respond to ICIs because they also lack cell-extrinsic cues required for an effective adaptive immune response (; ; Chen and Mellman, 2017), such as (1) a tumor microenvironment (TME) free from immunosuppressive cancer-associated fibroblast (CAF) subsets, tumor associated macrophages (TAMs) and/or myeloid-derived suppressor cells (MDSCs), and conducive to proper mobilization and recruitment of antigen presenting cells (APCs); and (2) appropriate ‘adjuvanticity’, characterized by the presence of immunostimulatory danger signals such as damage associated molecular patterns (DAMPs), that are necessary for activation of APCs, including dendritic cells (DCs) and stimulation of an effective cytotoxic T-cell (CTL) antitumor response (Galassi et al., 2024; Chen and Mellman, 2017; ; Sharma et al., 2017; Tumeh et al., 2014; Galluzzi et al., 2024). Collectively, these tumor cell-intrinsic and -extrinsic barriers define the limits of ICI efficacy and overcoming them holds the key to unlocking the full therapeutic potential of these otherwise-promising treatment modalities. Here, we discuss how ZBP1-driven immunogenic signaling can reverse these barriers, such that the as-yet unfulfilled curative potential of ICI-based therapies may be fully realized.
ZBP1-initiated signaling as a means to reverse ICI unresponsiveness
ZBP1 (previously known as DNA-dependent activator of IFN-regulatory factors, or DAI) is an interferon-stimulated gene (ISG) product (Takaoka et al., 2007). It has two N-terminal Zα domains, which selectively bind nucleic acids in the left-handed double-helical (Z) conformation (i.e., Z-NA species, both Z-RNA and Z-DNA) (Takaoka et al., 2007; Zhang et al., 2020; Herbert et al., 1993). It is likely that Z-NA binding by ZBP1 serves to oligomerize this protein, perhaps initially via Z-NA ‘bridging’, where two or more ZBP1 molecules associate with the same Z-NA molecule. This then allows RIP-Homology Interaction Motif (RHIM) -based self-association between the ZBP1 monomers, triggering oligomerization, liquid-liquid phase separation, condensate formation, and association with RIPK1/3 (Xie et al., 2024). Upon sensing Z-NAs, ZBP1 complexes with RIPK3 via homotypic interactions between the RHIMs found in both these proteins. Once RIPK3 associates with ZBP1, it becomes activated and phosphorylates Mixed Lineage Kinase Like protein (MLKL). Phosphorylated MLKL oligomerizes, homes to cellular membranes (including the plasma membrane) and forms pores in these membranes, triggering necroptosis, a potently immunogenic form of programmed cell death (Upton et al., 2017; ; Wang et al., 2014; Sun et al., 2012). In addition to activating the RIPK3-MLKL axis, ZBP1 can directly engage RIPK1 with the same RHIM-dependent interactions, thereby coupling Z-NA sensing to NF-κB-driven inflammatory transcription (Rebsamen et al., 2009; Kaiser et al., 2008; Thapa et al., 2016). During influenza A virus (IAV) and certain herpesvirus infections, the replicating virus generates nuclear Z-RNAs that are sensed by ZBP1, triggering a unique “inside-out” necroptotic program in which RIPK3 and MLKL are activated within the nucleus, leading to nuclear envelope rupture, leakage of genomic DNA into the cytosol, and subsequent necroptosis (Zhang et al., 2020; ; Yin et al., 2025). Interestingly, post-necroptotic cells (so-called ‘zombie’ cells) can continue to release cytokines and DAMPs long after membrane rupture, prolonging the inflammatory consequences of necroptotic demise (Orozco et al., 2019). ZBP1-activated necroptosis is thus a potently immunogenic form of programmed cell death.
Notably, ZBP1-RIPK3 signaling can also inflame tissues without triggering overt necroptosis, in at least three ways. First, the pores formed by MLKL can leak DAMPs and other inflammatory mediators without actually resulting in membrane rupture (Tait et al., 2026; Vucur et al., 2023). Because such ‘sub-lethal’ necroptosis does not result in the death of the cell, it may in fact sustain a more prolonged inflammatory outcome than what may occur following frank necroptosis. In such cells, ESCRT III-driven membrane repair may eventually remove damaged pMLKL+ membranes, preventing cell death (Gong et al., 2017). ESCRTIII-driven repair pathways are strikingly protective: for example, in murine L929 fibroblasts, they can continue to close MLKL-generated pores for at least 16 h in the continued presence of a strong necroptosis-activating stimulus (TNF + the caspase inhibitor zVAD) (Gong et al., 2017). In this timeframe, inactivation of the necroptotic stimulus can result in dephosphorylation of MLKL, complete reversal of phosphatidyl serine exposure on the outer leaflet of the plasma membrane, and, remarkably, a return to robust growth in culture of the resuscitated cell (Gong et al., 2017). Second, in some scenarios (such as IAV infections) cells that have been subjected to a necroptotic insult, and have survived it, manifest a persistently activated Type I IFN-driven inflammatory state for days or even weeks post insult (Heaton et al., 2014). Third, RIPK3 can directly activate NF-κB and IRF-3-driven inflammatory gene expression programs, independently of MLKL-driven membrane damage and necroptosis (Tait et al., 2026; Peng et al., 2022; Kofman et al., 2025), via engagement of RIPK1 and TRIF, respectively. These gene expression programs are fully manifest in cell types (such as cortical neurons) which appear intrinsically refractory to necroptotic membrane rupture (Kofman et al., 2025; Daniels et al., 2019; Daniels et al., 2017).
While such ZBP1-triggered necro-inflammatory responses can contribute to host defense and pathology in viral infections (Kofman et al., 2025; Daniels et al., 2019; Gautam et al., 2024), these same mechanisms may be therapeutically exploitable in cancer, where inducing ZBP1-driven necroptosis, as well as non-cytolytic inflammation, can overcome multiple barriers to ICI responsiveness (Zhang et al., 2022; Herbert and Balachandran, 2022; Snyder et al., 2019). The lytic nature of frank necroptosis ensures robust release of a rich repertoire of DAMPs and cytokines that activate innate immune sensing pathways, which can continue even after cell lysis (Orozco et al., 2019; Yatim et al., 2015). In tandem with RIPK1/3-mediated NF-κB- and IRF-3-dependent transcriptional programming, necroptotic cells can boost APC mobilization, activation, tumor antigen loading, and cross-priming of CD8+ T cells (Galluzzi et al., 2024; Snyder et al., 2019; Yatim et al., 2015), all of which are essential for a robust and sustainable ICI-driven anti-tumor immune responses (Zhang et al., 2022; Meier et al., 2024).
While ZBP1-initiated death signaling is frequently suppressed in tumor cells, often through epigenetic silencing of RIPK3, stromal elements within the TME have been shown to retain intact expression of the entire ZBP1-RIPK3 signaling machinery (Zhang et al., 2022; Herbert and Balachandran, 2022; Tang et al., 2025; Koo et al., 2015; He et al., 2009). In particular, inflammatory cancer-associated fibroblasts (iCAFs), may represent an especially vulnerable cell type for activation of ZBP1-dependent immunogenic (both lytic and non-lytic) signaling within cold TMEs (Herbert and Balachandran, 2022). Although an iCAF-enriched TME is characterized by increased frequencies of regulatory T cells, impaired cytolytic CD8+ T-cell activity, and extensive fibrotic remodeling (Gao et al., 2024; Ma et al., 2023; Desai et al., 2024; Kato et al., 2018; Kitamura et al., 2023), iCAFs themselves retain ZBP1/RIPK3 signaling competence (Zhang et al., 2022; Herbert and Balachandran, 2022). Indeed, preclinical studies have shown that activation of ZBP1 within iCAFs of the TME can potently reverse ICI unresponsiveness (Zhang et al., 2022; Herbert and Balachandran, 2022). Thus, ZBP1 activation within the TME can productively stimulate ICI-licensed antitumor responses, including in settings where the tumor cells themselves are deficient in ZBP1/RIPK3 signaling (Galluzzi et al., 2024; Zhang et al., 2022; Herbert and Balachandran, 2022).
The strong immunogenicity of ZBP1-initiated signaling pathways is rooted in the evolutionary programming of host defense mechanisms of mammals and other higher vertebrates. The adaptive immune system has evolved primarily to respond to pathogens, not tumors. The immunogenic pathways triggered by ZBP1 are de facto antiviral and antimicrobial defense mechanisms that not only eliminate the infected cell (thus preventing it from becoming a pathogen factory) but also provide immunogenic cues for full and timely activation of adaptive immune responses (Upton et al., 2017; Thomas et al., 2023).
Exploiting ZBP1-induced signaling to overcome ICI resistance
Emerging therapeutic modalities by which ZBP1-induced necroptosis can be activated for combinatorial use with ICIs are discussed below and summarized in
Figure 1;
Table 1.
ADAR1 inhibitors. The p150 isoform of ADAR1 is an enzyme that quenches Z-RNAs by binding and editing these Z-RNAs, thereby destabilizing them and preventing them from being sensed by ZBP1 (Zhang et al., 2022; Rehwinkel and Mehdipour, 2025; Jiao et al., 2022; de Reuver et al., 2022; Hubbard et al., 2022). ADAR1 inhibition is thus a promising strategy to unleash ZBP1 activation. Although no clinically-viable ADAR1 inhibitors yet exist, efforts to target the enzymatic function of ADAR1 are showing promise (Rehwinkel and Mehdipour, 2025). Notably, ADAR1 p150 quenches RNA not only by editing these RNAs, but also non-catalytically, by sequestering them (Zhang et al., 2022). Eliminating ADAR1 p150 expression is thus the preferred means of fully ablating its ability to keep Z-RNAs from triggering ZBP1. In this regard, all-trans retinoic acid (ATRA) has been shown to induce proteasomal degradation of ADAR1, thereby enhancing antitumor immunity and synergizing with PD-1 blockade to convert immunologically cold tumors into immune-responsive lesions (Li et al., 2024). More directly, ADAR1 p150 can be targeted for degradation by PROTAC- or molecular glue-based approaches. These strategies seek to tether ADAR1 p150 to cellular E3 ubiquitin ligases, prompting degradative ubiquitination and destruction of this ZBP1-suppressive protein. One such PROTAC (Z-PROTAC) has been shown to selectively degrade ADAR1, relieving inhibition of ZBP1 signaling (Wang Z. et al., 2024). Nuclear export inhibition using the XPO1 inhibitor Selinexor (KPT-330) sequesters ADAR1 p150 in the nucleus, relieving cytoplasmic suppression of ZBP1 (Karki et al., 2021). Selinexor has been demonstrated to promote beneficial ZBP1-dependent signaling during antitumor immunotherapeutic responses (Camilli et al., 2023), which may also result from trapping ZBP1 and its Z-NA ligands in the nucleus (Camilli et al., 2023; Jiao et al., 2020).
Small molecule Z-DNA inducers. Until clinically tractable ADAR1 p150 inhibitors are developed, one means by which ZBP1 can be activated, despite the presence of ADAR1 p150, is by inducing Z-DNA in cells. This is most readily done by converting B-DNA, the right-handed (Watson-Crick) double-helix, into Z-DNA, the left-handed isomer. The curaxin family member CBL0137 can induce the B→Z transition in genomic DNA (Zhang et al., 2022). ZBP1, which shuttles between the cytoplasm and nucleus, detects CBL0137-induced Z-DNA in the nucleus, activates RIPK3, and initiates necroptosis. Such necroptosis potently boosts ICI responses to cold tumors in preclinical animal models (Zhang et al., 2022; Liu et al., 2026), and is being assessed as ICI adjuvant in a Phase I study for refractory/recurrent melanoma, in combination with Nivolumab and Ipilimumab in melanoma (ClinicalTrials.gov identifier: NCT05498792). Although melanoma is amongst the most ICI-responsive solid tumors, approximately 30%–40% of patients demonstrate primary resistance to ICI-based monotherapy () and an additional 20%–25% eventually develop acquired resistance to this therapeutic modality (Hepner et al., 2024). This mixed landscape of ICI responsiveness, alongside either primary or acquired resistance to ICI therapies, makes refractory or recurrent melanoma a rational choice for examining if CBL0137 can reverse ICI resistance in this malignancy. Of note, CBL0137 can also deplete MDSCs within the TME, providing additional therapeutic benefit (Kim et al., 2024). Besides CBL0137, other agents, including mono-quinoxaline 3a (Saha et al., 2024) and spermine/sperminidine (Zhao et al., 2023), as well as ROS-mediated oxidative stress and consequent mitochondrial DNA oxidation (Song et al., 2025; Yang et al., 2026), have each been reported to induce the B→Z transition in DNA, and may also therefore function as ZBP1 agonists in vivo, although studies demonstrating these molecules (or approaches) can potentiate ICI responsiveness in a ZBP1-dependent manner are still lacking. Furthermore, their translation will require confirmation that they do indeed generate Z-NA intratumorally, and at tolerable exposures.
Small molecule Z-RNA inducers. The human genome is replete with endogenous retroelements (EREs), many of which can form Z-RNA when reactivated or otherwise expressed as RNAs (Yin et al., 2025; DeAntoneo et al., 2023). These Z-RNA forming EREs are sometimes embedded within introns and 3′UTRs of protein coding mRNAs and are also found in great abundance in intergenic regions of the genome. Small molecule interventions that allow accrual of both intragenic (i.e., intronic/3′UTR) and intergenic Z-forming EREs are an emerging means of activating ZBP1. For example, agents capable of inducing oxidative stress, such as sodium arsenite and cisplatin, can induce endogenous Z-RNA and activate ZBP1 in tumors (Yang et al., 2023). Promisingly, pharmacologic or genetic inhibition of the spliceosome machinery (e.g., SF3B1 inhibition via pladienolide B) has been shown to induce widespread intron retention and consequent accumulation of intronic ERE-derived Z-RNAs. These Z-RNAs are directly sensed by ZBP1, triggering RIPK3-dependent necroptosis (Yang et al., 2025; He et al., 2025; Jiang et al., 2025). In small cell lung cancer models, spliceosome inhibition induced robust ZBP1-dependent cell death in necroptosis-competent tumor cells and CAFs, reduced tumor growth in vivo, and enhanced ICI responsiveness in a ZBP1-dependent manner (Jiang et al., 2025). Interestingly, spliceosome inhibition induces nuclear accumulation of RNA:DNA hybrids that also adopt the left-handed Z-conformation and are sensed by ZBP1 (He et al., 2025). These findings identify RNA splicing fidelity as a critical checkpoint restraining endogenous Z-NA accumulation and establish spliceosome perturbation as a potent strategy to activate ZBP1. Analogously, interfering with the termination of mRNA transcription can cause ERE-derived Z-RNAs to accrue. The 3′ ends of mRNAs are typically truncated and polyadenylated by a multi-protein complex called Cleavage and Polyadenylation Specificity Factor (CPSF). When CPSF activity is disrupted, RNA Polymerase II fails to terminate transcription at canonical polyadenylation sequence (PAS) sites, and pre-mRNAs with enormously lengthy 3′ extensions are generated (Rosa-Mercado and Steitz, 2022; Proudfoot, 2016). These aberrantly elongated RNAs accumulate in the nucleus and are often replete with Z-forming ERE sequences capable of activating ZBP1 (Yin et al., 2025). Indeed, during IAV and HSV-1 infections, both of which result in disrupted CPSF activity, these host cell-derived Z-RNAs are major and bona fide ZBP1 ligands (Yin et al., 2025). The CPSF component CPSF3 is the nuclease which truncates pre-mRNAs after the PAS, and this nuclease can be inhibited by small-molecule approaches. Pharmacological inhibition of CPSF activity using the CPSF3 inhibitor JTE-607 is an effective means of inducing Z-RNA and activating ZBP1 (Yin et al., 2025). Relatedly, ablation of the XRN1, the 5′-3′ exoribonuclease responsible degrading excess Pol II-generated RNA after CPSF3-mediated cleavage of the authentic transcript, also results is rampant accrual of dsRNA (Zou et al., 2024). Disruptors of mRNA 3′ processing thus represent an additional means (i.e., besides spliceosome inhibition) of generating Z-RNA and activating ZBP1, ripe for combinatorial deployment with ICI in immune cold tumors.
Oncolytic viruses. Oncolytic viruses represent a particularly relevant class of ZBP1-activating agents. Whereas classically many of these viruses were thought to induce apoptotic death of tumor cells, several viruses with oncolytic potential also activate ZBP1 and/or induce necroptosis. For example, herpes simplex virus-1 (HSV-1), the backbone of talimogene laherparepvec (T-VEC), an FDA-approved oncolytic agent for advanced melanoma (), generates copious amounts of Z-RNA in cells (Yin et al., 2025; Wang S. et al., 2024). While some of these Z-RNAs are produced by viral transcripts, most arise from disrupted termination of host pre-mRNAs (the HSV-1 protein ICP27 blocks CPSF activity). These Z-RNAs are potent ZBP1 ligands, but because HSV-1 also encodes a RHIM-containing protein (ICP6) that blocks ZBP1-RIPK3 signaling in human cells (Guo et al., 2015), the full necroptosis-activating potential of T-VEC or other oncolytic HSV-1 platforms (Workenhe et al., 2020) may yet remain to be realized (Ribas et al., 2017; Chesney et al., 2023). We suggest that HSV-1 variants with the ICP6 RHIM rendered non-functional by mutation will be even more powerful ICI adjuvants than T-VEC itself (Yin et al., 2025), and nominate this strategy for fast tracking as an especially actionable means of provoking beneficial necroinflammation within tumors. Similarly, mammalian orthoreovirus (ReoV) have significant potential as an oncolytic agent, and the ReoV-based oncolytic virus Pelareorep (Reolysin) has shown promise in an early phase clinical trial for PDAC (Mahalingam et al., 2020) (in combination with ICIs), and in HR+/HER2-metastatic breast cancers (Clark et al., 2025), with further studies ongoing in other malignancies (Modest et al., 2025). Like HSV-1, ReoV induces necroptotic cell death (; ; DeAntoneo et al., 2022), but whether this is because ReoV produces Z-RNA and activates ZBP1 remains to be seen (DeAntoneo et al., 2023). Of note, IAV have also been assessed for oncolytic activity and have shown some promise in this regard (Hamilton et al., 2018; ). IAV infections also generate Z-RNA and activate ZBP1, because this virus can potently disrupt CPSF activity via its NS1 protein (Zhang et al., 2020; Yin et al., 2025; ). IAV, and other orthomyxoviruses, represent a currently untapped means of triggering ZBP1 for immunotherapeutic benefit.
FIGURE 1
TABLE 1
| Therapeutic strategy | Representative benchmark agent(s) | Mode of ZBP1 agonism | Predominant ZBP1 ligand generated | References |
|---|---|---|---|---|
| ADAR1 inhibition | ATRA | | Z-RNA | Li et al. (2024) |
| ADAR1-directed PROTACs/ molecular glues | ADAR1 p150 degradation | Z-RNA | Wang Z. et al. (2024) | |
| Selinexor/KPT-330 | Prevention or ADAR1 p150 export to cytoplasm | Z-RNA | Karki et al. (2021), Camilli et al. (2023), Jiao et al. (2020) | |
| Z-DNA induction | CBL0137 | B→Z transition of genomic DNA | Z-DNA | Zhang et al. (2022), Liu et al. (2026) |
| Mono-quinoxaline | ? | Z-DNA | Saha et al. (2024) | |
| Spermine/spermidine | ? | Z-DNA | Zhao et al. (2023) | |
| Oxidative stress | B→Z transition of mitochondrial DNA | Z-DNA | Song et al. (2025), Yang et al. (2026) | |
| Z-RNA induction | Pladienolide B | Spliceosome inhibition | Z-RNA RNA: DNA hybrids | Yang et al. (2025), He et al. (2025), Jiang et al. (2025) |
| JTE-607 | CPSF disruption | Z-RNA | Yin et al. (2025) | |
| Oncolytic viruses | Oncolytic HSV-1 (talimogene laherparepvec) | Virus- and host-derived Z-NAs | Z-RNA, Z-DNA | Yin et al. (2025), Wang S. et al. (2024) |
| Oncolytic reovirus (pelareorep) | ? | Z-RNA? | Mahalingam et al. (2020), Clark et al. (2025), Modest et al. (2025) | |
| Oncolytic influenza A virus | Virus- and host- derived Z-NAs | Z-RNA | Zhang et al. (2020), Yin et al. (2025), Hamilton et al. (2018), , |
Strategies to activate ZBP1-initiates immunogenic signaling for cancer immunotherapy of tumors. ZBP1 agonist strategies include ADAR1 inhibitors and degraders, pharmacological and other means of Z-DNA and Z-RNA formation, and oncolytic viruses that can generate Z-NA species in infected cells.
Discussion and concluding remarks
The therapeutic strategies reviewed above converge on the idea that ZBP1 driven signaling, whether induced in tumor cells or in cells of the TME, can serve to inflame immunologically cold tumors and promote durable ICI-responsive anti-tumor immunity. Tumors characterized by an immune-excluded phenotype, including pancreatic adenocarcinoma, cholangiocarcinoma, and desmoplastic melanoma, represent compelling initial targets. In these settings, CAF-driven stromal architecture forms a dominant barrier to immune infiltration. Activation of ZBP1 within these compartments may dismantle these stromal ‘walls’, enabling CTLs and other immune effector cells (NK cells, γδ T cells) access to tumor nests and simultaneously providing the requisite antigenic and adjuvant cues that overcome barrier-mediated resistance (; Chen and Mellman, 2017). Importantly, the idea of leveraging ZBP1-initiated signaling for immunotherapeutic benefit is not limited to immune-excluded tumors. In tumors with immune-desert phenotypes, where deficiencies in antigenicity and adjuvanticity predominate (Chen and Mellman, 2017), ZBP1-driven signaling may initiate a self-amplifying cycle of immunogenic cell death and necroinflammation, seeding de novo immune responses that propagate through antigen release, DC activation, and T-cell priming (Galluzzi et al., 2024; Yin et al., 2025; Zhang et al., 2022; Galluzzi et al., 2026; Ishizuka et al., 2019).
Toxicity is a legitimate concern since ZBP1-driven necroptosis is not an innocuous process. During severe influenza, as a case in point, it is responsible for pulmonary immunopathology that characterizes severe disease (Zhang et al., 2020; ; Yin et al., 2025; Gautam et al., 2024). Systemic induction of ZBP1 activity therefore carries a meaningful risk of off-tumor necro-inflammatory injury, particularly in necroptosis-prone tissues, such as the those of the lung and gastrointestinal epithelium. This risk can be mitigated by staggering the administration of the ZBP1 activating modality with agents that will locally boost ZBP1 levels, and with the ICI therapies themselves.
For example, a ‘prime-trigger-release’ therapeutic paradigm, in which tumors are first primed to express ZBP1 within cells of the TME (e.g., via localized/intra-tumoral delivery of type I or type II IFN). An example of a clinically actionable strategy to achieve this is by use of replication deficient adenovirus encoding human IFN-γ that is suitable for safe intra-tumoral administration (Siller et al., 2026). Once ZBP1 is induced in tumor tissues, its activation is subsequently triggered, for example, via pharmacologic induction of Z-NA accumulation (e.g., using CBL0137 or CPSF3 inhibitors). Finally, the tumor antigens and danger signals released by ZBP1 signaling are allowed to propagate systemically through the anti-tumor immunity cycle, in the presence of ICI.
Such a strategy, by enabling localized activation of ZBP1 in select tumor sites, achieves broader systemic tumor control (akin to an in situ abscopal-like effect), without the attendant risks of necroinflammation from systemic administration of the necroptosis inducing agent. With these caveats, ZBP1 signaling presents as a uniquely actionable therapeutic entry point that can be engaged through diverse, mechanistically defined strategies for the express purpose of converting immunologically cold tumors into durably ICI-responsive neoplasms.
Statements
Author contributions
PD: Writing – review and editing, Writing – original draft, Conceptualization. CW: Visualization, Writing – review and editing, Writing – original draft. SB: Funding acquisition, Writing – original draft, Conceptualization, Writing – review and editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. Work in the S.B. lab is supported by NIH R01 grants AI135025, AI144400, AI161624, and CA168621. Additional support is provided by NIH Cancer Center Support Grant P30CA006927.
Acknowledgments
We acknowledge Lorenzo Galluzzi and Riley Williams for their comments on this manuscript.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1
AlsaafeenB. H.AliB. R.ElkordE. (2025). Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol. Cancer24, 20. 10.1186/s12943-024-02212-7
2
AmaralT.SeeberO.MersiE.SanchezS.ThomasI.MeiwesA.et al (2020). Primary resistance to PD-1-Based Immunotherapy-A study in 319 patients with stage IV melanoma. Cancers (Basel)12, 1027. 10.3390/cancers12041027
3
AndersonA. C.JollerN.KuchrooV. K. (2016). Lag-3, Tim-3, and TIGIT: co-Inhibitory receptors with specialized functions in immune regulation. Immunity44, 989–1004. 10.1016/j.immuni.2016.05.001
4
AndtbackaR. H.KaufmanH. L.CollichioF.AmatrudaT.SenzerN.ChesneyJ.et al (2015). Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol.33, 2780–2788. 10.1200/JCO.2014.58.3377
5
BagaevA.KotlovN.NomieK.SvekolkinV.GafurovA.IsaevaO.et al (2021). Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell39, 845–865 e847. 10.1016/j.ccell.2021.04.014
6
BalachandranS.MocarskiE. S. (2021). Viral Z-RNA triggers ZBP1-dependent cell death. Curr. Opin. Virol.51, 134–140. 10.1016/j.coviro.2021.10.004
7
BauerD. L. V.TellierM.Martínez-AlonsoM.NojimaT.ProudfootN. J.MurphyS.et al (2018). Influenza virus mounts a two-pronged attack on host RNA polymerase II transcription. Cell Rep.23, 2119–2129 e2113. 10.1016/j.celrep.2018.04.047
8
BergerA. K.DanthiP. (2013). Reovirus activates a caspase-independent cell death pathway. mBio4, e00178–00113. 10.1128/mBio.00178-13
9
BergerA. K.HillerB. E.TheteD.SnyderA. J.PerezE.UptonJ. W.et al (2017). Viral RNA at two stages of reovirus infection is required for the induction of necroptosis. J. Virol.91, JVI.02404. 10.1128/JVI.02404-16
10
BergmannM.RomirerI.SachetM.FleischhackerR.García-SastreA.PaleseP.et al (2001). A genetically engineered influenza A virus with ras-dependent oncolytic properties. Cancer Res.61, 8188–8193.
11
BinnewiesM.RobertsE. W.KerstenK.ChanV.FearonD. F.MeradM.et al (2018). Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med.24, 541–550. 10.1038/s41591-018-0014-x
12
BrahmerJ.ReckampK. L.BaasP.CrinòL.EberhardtW. E. E.PoddubskayaE.et al (2015). Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med.373, 123–135. 10.1056/NEJMoa1504627
13
CamilliS.LockeyR.KolliputiN. (2023). Nuclear export inhibitors selinexor (KPT-330) and Eltanexor (KPT-8602) provide a novel therapy to reduce tumor growth by induction of PANoptosis. Cell Biochem. Biophys.81, 421–426. 10.1007/s12013-023-01135-2
14
ChenD. S.MellmanI. (2017). Elements of cancer immunity and the cancer-immune set point. Nature541, 321–330. 10.1038/nature21349
15
ChesneyJ. A.RibasA.LongG. V.KirkwoodJ. M.DummerR.PuzanovI.et al (2023). Randomized, double-blind, placebo-controlled, global phase III trial of talimogene laherparepvec combined with pembrolizumab for advanced melanoma. J. Clin. Oncol.41, 528–540. 10.1200/JCO.22.00343
16
ClarkA. S.ZhaoF.KleinP.MonteroA. J.FalksonC.Krill-JacksonE.et al (2025). A phase II randomized study of paclitaxel alone or combined with pelareorep with or without avelumab in metastatic hormone receptor-positive breast cancer: the BRACELET-01/PrE0113 study. Clin. Cancer Res.31, 2655–2662. 10.1158/1078-0432.CCR-24-2701
17
DanielsB. P.SnyderA. G.OlsenT. M.OrozcoS.OguinT. H.TaitS. W. G.et al (2017). RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation. Cell169, 301–313 e311. 10.1016/j.cell.2017.03.011
18
DanielsB. P.KofmanS. B.SmithJ. R.NorrisG. T.SnyderA. G.KolbJ. P.et al (2019). The nucleotide sensor ZBP1 and kinase RIPK3 induce the enzyme IRG1 to promote an antiviral metabolic state in neurons. Immunity50, 64–76 e64. 10.1016/j.immuni.2018.11.017
19
de ReuverR.VerdonckS.DierickE.NemegeerJ.HessmannE.AhmadS.et al (2022). ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. Nature607, 784–789. 10.1038/s41586-022-04974-w
20
DeAntoneoC.DanthiP.BalachandranS. (2022). Reovirus activated cell death pathways. Cells11, 1757. 10.3390/cells11111757
21
DeAntoneoC.HerbertA.BalachandranS. Z.- (2023). Form nucleic acid-binding protein 1 (ZBP1) as a sensor of viral and cellular Z-RNAs: walking the razor's edge. Curr. Opin. Immunol.83, 102347. 10.1016/j.coi.2023.102347
22
DesaiP.TakahashiN.KumarR.NicholsS.MalinJ.HuntA.et al (2024). Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities. Cell Rep. Med.5, 101610. 10.1016/j.xcrm.2024.101610
23
GalassiC.ChanT. A.VitaleI.GalluzziL. (2024). The hallmarks of cancer immune evasion. Cancer Cell42, 1825–1863. 10.1016/j.ccell.2024.09.010
24
GalluzziL.GuilbaudE.SchmidtD.KroemerG.MarincolaF. M. (2024). Targeting immunogenic cell stress and death for cancer therapy. Nat. Rev. Drug Discov.23, 445–460. 10.1038/s41573-024-00920-9
25
GalluzziL.KeppO.ZitvogelL.TangD.KroemerG. (2026). Cancer cell death: cell-Autonomous and immunogenic dimensions. Cancer Cell44, 281–305. 10.1016/j.ccell.2025.12.005
26
GaoY.LiJ.ChengW.DiaoT.LiuH.BoY.et al (2024). Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation. Cancer Cell42, 1764–1783 e1710. 10.1016/j.ccell.2024.08.020
27
GautamA.BoydD. F.NikharS.ZhangT.SiokasI.Van de VeldeL. A.et al (2024). Necroptosis blockade prevents lung injury in severe influenza. Nature628, 835–843. 10.1038/s41586-024-07265-8
28
GongY. N.GuyC.OlausonH.BeckerJ. U.YangM.FitzgeraldP.et al (2017). ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell169, 286–300 e216. 10.1016/j.cell.2017.03.020
29
GuoH.OmotoS.HarrisP. A.FingerJ. N.BertinJ.GoughP. J.et al (2015). Herpes simplex virus suppresses necroptosis in human cells. Cell Host Microbe17, 243–251. 10.1016/j.chom.2015.01.003
30
HamiltonJ. R.VijayakumarG.PaleseP. A. (2018). Recombinant antibody-expressing influenza virus delays tumor growth in a mouse model. Cell Rep.22, 1–7. 10.1016/j.celrep.2017.12.025
31
HeS.WangL.MiaoL.WangT.DuF.ZhaoL.et al (2009). Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-Alpha. Cell137, 1100–1111. 10.1016/j.cell.2009.05.021
32
HeJ.ZhuY.TianZ.LiuM.GaoA.FuW.et al (2025). ZBP1 senses spliceosome stress through Z-RNA:DNA hybrid recognition. Mol. Cell85, 1790–1805 e1797. 10.1016/j.molcel.2025.04.004
33
HeatonN. S.LangloisR. A.SachsD.LimJ. K.PaleseP.tenOeverB. R. (2014). Long-term survival of influenza virus infected club cells drives immunopathology. J. Exp. Med.211, 1707–1714. 10.1084/jem.20140488
34
HepnerA.VersluisJ. M.WallaceR.AllayousC.BrownL. J.TrojanielloC.et al (2024). The features and management of acquired resistance to PD1-based therapy in metastatic melanoma. Eur. J. Cancer196, 113441. 10.1016/j.ejca.2023.113441
35
HerbertA.BalachandranS. (2022). Z-DNA enhances immunotherapy by triggering death of inflammatory cancer-associated fibroblasts. J. Immunother. Cancer10, e005704. 10.1136/jitc-2022-005704
36
HerbertA. G.SpitznerJ. R.LowenhauptK.RichA. (1993). Z-DNA binding protein from chicken blood nuclei. Proc. Natl. Acad. Sci. U. S. A.90, 3339–3342. 10.1073/pnas.90.8.3339
37
HubbardN. W.AmesJ. M.MauranoM.ChuL. H.SomflethK. Y.GokhaleN. S.et al (2022). ADAR1 mutation causes ZBP1-dependent immunopathology. Nature607, 769–775. 10.1038/s41586-022-04896-7
38
IshizukaJ. J.MangusoR. T.CheruiyotC. K.BiK.PandaA.Iracheta-VellveA.et al (2019). Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature565, 43–48. 10.1038/s41586-018-0768-9
39
JiangX.MaX.ZhouY.LiuX.ZhangT.KimW.et al (2025). Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer. Cell Rep.44, 116384. 10.1016/j.celrep.2025.116384
40
JiaoH.WachsmuthL.KumariS.SchwarzerR.LinJ.ErenR. O.et al (2020). Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation. Nature580, 391–395. 10.1038/s41586-020-2129-8
41
JiaoH.WachsmuthL.WolfS.LohmannJ.NagataM.KayaG. G.et al (2022). ADAR1 averts fatal type I interferon induction by ZBP1. Nature607, 776–783. 10.1038/s41586-022-04878-9
42
KaiserW. J.UptonJ. W.MocarskiE. S. (2008). Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-Dependent activator of IFN regulatory factors. J. Immunol.181, 6427–6434. 10.4049/jimmunol.181.9.6427
43
KarkiR.SundaramB.SharmaB. R.LeeS.MalireddiR. S.NguyenL. N.et al (2021). ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis. Cell Rep.37, 109858. 10.1016/j.celrep.2021.109858
44
KatoT.NomaK.OharaT.KashimaH.KatsuraY.SatoH.et al (2018). Cancer-Associated fibroblasts affect intratumoral CD8(+) and FoxP3(+) T cells Via IL6 in the tumor microenvironment. Clin. Cancer Res.24, 4820–4833. 10.1158/1078-0432.CCR-18-0205
45
KimM.PowersC. A.FisherD. T.KuA. W.NeznanovN.SafinaA. F.et al (2024). Enhancing Anti-PD-1 immunotherapy by targeting MDSCs via hepatic arterial infusion in breast cancer liver metastases. Cancers (Basel)16, 3711. 10.3390/cancers16213711
46
KitamuraF.SembaT.Yasuda-YoshiharaN.YamadaK.NishimuraA.YamasakiJ.et al (2023). Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer. JCI Insight8, e163022. 10.1172/jci.insight.163022
47
KofmanS. B.ChuL. H.AmesJ. M.ChavarriaS. D.LichaucoK.DanielsB. P.et al (2025). RIPK3 coordinates RHIM domain-dependent antiviral inflammatory transcription in neurons. Sci. Signal18, eado9745. 10.1126/scisignal.ado9745
48
KooG. B.MorganM. J.LeeD. G.KimW. J.YoonJ. H.KooJ. S.et al (2015). Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res.25, 707–725. 10.1038/cr.2015.56
49
LiC. F.BaiL. Y.WeiY.LeeH. H.YangR.YaoJ.et al (2024). All-trans retinoic acid-mediated ADAR1 degradation synergizes with PD-1 blockade to suppress pancreatic cancer. bioRxiv. 10.1101/2024.10.20.619300
50
LiuH.HeQ.WangD. X.LiuJ.QuY.ZhangD.et al (2026). Delivery of a ZBP1 agonist enhances radiotherapy-induced antitumour immunity in hepatocellular carcinoma. J. Control Release395, 114991. 10.1016/j.jconrel.2026.114991
51
MaC.YangC.PengA.SunT.JiX.MiJ.et al (2023). Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment. Mol. Cancer22, 170. 10.1186/s12943-023-01876-x
52
MahalingamD.WilkinsonG. A.EngK. H.FieldsP.RaberP.MoseleyJ. L.et al (2020). Pembrolizumab in combination with the oncolytic virus pelareorep and chemotherapy in patients with advanced pancreatic adenocarcinoma: a phase Ib Study. Clin. Cancer Res.26, 71–81. 10.1158/1078-0432.CCR-19-2078
53
MeierP.LegrandA. J.AdamD.SilkeJ. (2024). Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity. Nat. Rev. Cancer24, 299–315. 10.1038/s41568-024-00674-x
54
MittalD.GubinM. M.SchreiberR. D.SmythM. J. (2014). New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr. Opin. Immunol.27, 16–25. 10.1016/j.coi.2014.01.004
55
ModestD. P.GoekkurtE.HeinemanT. C.MartensU. M.Reinacher-SchickA. C.ChaterJ.et al (2025). GOBLET platform study: preliminary safety and tumor response results for the relapsed anal carcinoma cohort in patients treated with pelareorep and atezolizumab. J. Clin. Oncol.43, 6. 10.1200/JCO.2025.43.4_suppl.6
56
OrozcoS. L.DanielsB. P.YatimN.MessmerM. N.QuaratoG.Chen-HarrisH.et al (2019). RIPK3 activation leads to cytokine synthesis that continues after loss of cell membrane integrity. Cell Rep.28, 2275–2287 e2275. 10.1016/j.celrep.2019.07.077
57
PengR.WangC. K.Wang‐KanX.IdornM.KjærM.ZhouF. Y.et al (2022). Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1. EMBO Rep.23, e55839. 10.15252/embr.202255839
58
PilardC.AncionM.DelvenneP.JerusalemG.HubertP.HerfsM. (2021). Cancer immunotherapy: it's time to better predict patients' response. Br. J. Cancer125, 927–938. 10.1038/s41416-021-01413-x
59
ProudfootN. J. (2016). Transcriptional termination in mammals: stopping the RNA polymerase II juggernaut. Science352, aad9926. 10.1126/science.aad9926
60
RebsamenM.HeinzL. X.MeylanE.MichalletM. C.SchroderK.HofmannK.et al (2009). DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep.10, 916–922. 10.1038/embor.2009.109
61
RehwinkelJ.MehdipourP. (2025). ADAR1: from basic mechanisms to inhibitors. Trends Cell Biol.35, 59–73. 10.1016/j.tcb.2024.06.006
62
RibasA.DummerR.PuzanovI.VanderWaldeA.AndtbackaR. H. I.MichielinO.et al (2017). Oncolytic virotherapy promotes intratumoral T cell infiltration and improves Anti-PD-1 immunotherapy. Cell170, 1109–1119 e1110. 10.1016/j.cell.2017.08.027
63
RobertC.LongG. V.BradyB.DutriauxC.MaioM.MortierL.et al (2015). Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med.372, 320–330. 10.1056/NEJMoa1412082
64
Rosa-MercadoN. A.SteitzJ. A. (2022). Who let the DoGs out? - biogenesis of stress-induced readthrough transcripts. Trends Biochem. Sci.47, 206–217. 10.1016/j.tibs.2021.08.003
65
SahaR.PalR.GangulyB.MajhiB.DuttaS. (2024). Mono-quinoxaline-induced DNA structural alteration leads to ZBP1/RIP3/MLKL-driven necroptosis in cancer cells. Eur. J. Med. Chem.270, 116377. 10.1016/j.ejmech.2024.116377
66
SharmaP.Hu-LieskovanS.WargoJ. A.RibasA. (2017). Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell168, 707–723. 10.1016/j.cell.2017.01.017
67
SillerG.BalachandranS.GohM.IbrahimS.KreppelF.KhosrotehraniK.et al (2026). Evaluation of adnexal features and histological response to intralesional SP-002 in nodular basal cell carcinoma. J. Clin. Oncol.44, 2596. 10.1200/JCO.2026.44.16_suppl.2596
68
SnyderA. G.HubbardN. W.MessmerM. N.KofmanS. B.HaganC. E.OrozcoS. L.et al (2019). Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity. Sci. Immunol.4, eaaw2004. 10.1126/sciimmunol.aaw2004
69
SongZ.XieX.ChenY.ZhangB.LiX.YangY.et al (2025). Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease. Immunity58, 2574–2592.e2579. 10.1016/j.immuni.2025.07.024
70
SunL.WangH.WangZ.HeS.ChenS.LiaoD.et al (2012). Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell148, 213–227. 10.1016/j.cell.2011.11.031
71
TaitS. W. G.OberstA. (2026). Cellular memory of sub-lethal stress. Immunity59, 801–812. 10.1016/j.immuni.2026.02.017
72
TakaokaA.WangZ.ChoiM. K.YanaiH.NegishiH.BanT.et al (2007). DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature448, 501–505. 10.1038/nature06013
73
TangJ.ZhuangY.ZhangY.HuH.WangH.XuH.et al (2025). Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications. J. Hematol. Oncol.18, 77. 10.1186/s13045-025-01726-x
74
ThapaR. J.IngramJ. P.RaganK. B.NogusaS.BoydD. F.BenitezA. A.et al (2016). DAI senses influenza A virus genomic RNA and activates RIPK3-Dependent cell death. Cell Host Microbe20, 674–681. 10.1016/j.chom.2016.09.014
75
ThomasP. G.ShubinaM.BalachandranS. (2023). ZBP1/DAI-Dependent cell death pathways in influenza A virus immunity and pathogenesis. Curr. Top. Microbiol. Immunol.442, 41–63. 10.1007/82_2019_190
76
TumehP. C.HarviewC. L.YearleyJ. H.ShintakuI. P.TaylorE. J. M.RobertL.et al (2014). PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature515, 568–571. 10.1038/nature13954
77
UptonJ. W.ShubinaM.BalachandranS. (2017). RIPK3-driven cell death during virus infections. Immunol. Rev.277, 90–101. 10.1111/imr.12539
78
VucurM.GhallabA.SchneiderA. T.AdiliA.ChengM.CastoldiM.et al (2023). Sublethal necroptosis signaling promotes inflammation and liver cancer. Immunity56, 1578–1595 e1578. 10.1016/j.immuni.2023.05.017
79
WangH.SunL.SuL.RizoJ.LiuL.WangL. F.et al (2014). Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell54, 133–146. 10.1016/j.molcel.2014.03.003
80
WangZ.ZhangD.QiuX.InuzukaH.XiongY.LiuJ.et al (2024a). Structurally specific Z-DNA proteolysis targeting chimera enables targeted degradation of adenosine deaminase acting on RNA 1. J. Am. Chem. Soc.146, 7584–7593. 10.1021/jacs.3c13646
81
WangS.SongA.XieJ.WangY. Y.WangW. D.ZhangM. J.et al (2024b). Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity. Nat. Commun.15, 3669. 10.1038/s41467-024-48032-7
82
WorkenheS. T.NguyenA.BakhshinyanD.WeiJ.HareD. N.MacNeillK. L.et al (2020). De novo necroptosis creates an inflammatory environment mediating tumor susceptibility to immune checkpoint inhibitors. Commun. Biol.3, 645. 10.1038/s42003-020-01362-w
83
XieF.WuD.HuangJ.LiuX.ShenY.HuangJ.et al (2024). ZBP1 condensate formation synergizes Z-NAs recognition and signal transduction. Cell Death Dis.15, 487. 10.1038/s41419-024-06889-y
84
YangT.WangG.ZhangM.HuX.LiQ.YunF.et al (2023). Triggering endogenous Z-RNA sensing for anti-tumor therapy through ZBP1-dependent necroptosis. Cell Rep.42, 113377. 10.1016/j.celrep.2023.113377
85
YangZ. H.WuP.ZhangB. X.YangC. R.HuangJ.WuL.et al (2025). ZBP1 senses splicing aberration through Z-RNA to promote cell death. Mol. Cell85, 1775–1789 e1775. 10.1016/j.molcel.2025.03.023
86
YangZ.-H.ZhangB.-X.YeH.-F.ShiL.GongR.CaiZ.-Y.et al (2026). Oxidation-Driven mtDNA BZ Transition Activates ZBP1 to Mediate Acetaminophen Hepatotoxicity. Vita. 10.15302/vita.2026.04.0029
87
YatimN.Jusforgues-SaklaniH.OrozcoS.SchulzO.Barreira da SilvaR.Reis e SousaC.et al (2015). RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8(+) T cells. Science350, 328–334. 10.1126/science.aad0395
88
YinC.FedorovA.GuoH.CrawfordJ. C.RousseauC.ZhongX.et al (2025). Host cell Z-RNAs activate ZBP1 during virus infections. Nature648, 707–716. 10.1038/s41586-025-09705-5
89
ZhangT.YinC.BoydD. F.QuaratoG.IngramJ. P.ShubinaM.et al (2020). Influenza virus Z-RNAs induce ZBP1-Mediated necroptosis. Cell180, 1115–1129 e1113. 10.1016/j.cell.2020.02.050
90
ZhangT.YinC.FedorovA.QiaoL.BaoH.BeknazarovN.et al (2022). ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature606, 594–602. 10.1038/s41586-022-04753-7
91
ZhaoC.MaY.ZhangM.GaoX.LiangW.QinY.et al (2023). Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity. Immunity56, 2508–2522 e2506. 10.1016/j.immuni.2023.09.012
92
ZouT.ZhouM.GuptaA.ZhuangP.FishbeinA. R.WeiH. Y.et al (2024). XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells. Cell Rep.43, 113783. 10.1016/j.celrep.2024.113783
Summary
Keywords
cancer immunotherapy, mlkl, necroptosis, ripk3, ZBP1, Z-DNA, Z-RNA
Citation
Desai P, Wen C and Balachandran S (2026) Leveraging ZBP1 signaling for cancer immunotherapy. Front. Cell Death 5:1841599. doi: 10.3389/fceld.2026.1841599
Received
28 March 2026
Revised
18 June 2026
Accepted
30 June 2026
Published
22 July 2026
Volume
5 - 2026
Edited by
Bertrand Mollereau, Université de Lyon, France
Reviewed by
Elena Catanzaro, Ghent University, Belgium
Manal Kanaan, Middle Technical University, Iraq
Updates
Copyright
© 2026 Desai, Wen and Balachandran.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Parth Desai, parth.desai@fccc.edu; Siddharth Balachandran, siddharth.balachandran@fccc.edu
Disclaimer
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