ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation

Yang, Yong; Wu, Meng; Cao, Dongqing; Yang, Chao; Jin, Jingsi; Wu, Lingling; Hong, Xiaochuan; Li, Wenwen; Lu, Lu; Li, Jinmei; Wang, Xinran; Meng, Xiangjiao; Zhang, Zhen; Cheng, Jinke; Ye, Youqiong; Xiao, Hui; Yu, Jinming; Deng, Lu

doi:10.1126/sciadv.abf6290

Cited by 99 publications

(68 citation statements)

References 47 publications

(77 reference statements)

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“…ZBP1 is a well-appreciated driver of receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis, an inflammatory form of cell death that can be induced by interferon that can feed forward to potentiate IFN-I and pro-inflammatory responses (Baik et al, 2021; Devos et al, 2020; Ingram et al, 2019; Jiao et al, 2020; Sridharan et al, 2017; Yang et al, 2021). Although MLKL was slightly increased, other necroptosis factors were not elevated in Tfam +/- MEFs (Figure S1J).…”

Section: Resultsmentioning

confidence: 99%

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Lei

VanPortfliet

Chen

et al. 2022

Preprint

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Mitochondrial DNA (mtDNA) is a potent agonist of the cyclic GMP-AMP (cGAMP) synthase (cGAS)-Stimulator of Interferon Genes (STING)-type I interferon (IFN-I) pathway. However, the kinetics of mtDNA detection by cGAS or other nucleic acid sensors and the exact immunostimulatory features of mtDNA remain poorly defined. Here, we show that robust and sustained IFN-I responses downstream of mtDNA stress require the nucleic acid sensor Z-DNA binding protein 1 (ZBP1) in a cell death independent manner. Cells experiencing persistent mtDNA release display robust ZBP1 expression, as well as a marked increase in the cytoplasmic pool of cGAS. Biochemical and microscopy analyses reveal that the receptor-interacting protein homotypic interaction motif (RHIMs) of ZBP1 bind the N-terminus of cGAS, leading to its entrapment in the cytoplasm. Moreover, we show that genetic and pharmacologic induction of mtDNA stress leads to the mitochondrial and cytoplasmic accumulation of Z-form DNA. Nuclease treatment or deletion of Z-DNA binding domains of ZBP1 reduces its interaction with cGAS and impairs cGAMP production downstream of mtDNA stress. Finally, we uncover that ZBP1 is a novel regulator of IFN-I-mediated disease pathology, working in tandem with the cGAS-STING pathway to sense mtDNA instability and sustain IFN-I signaling that contributes to cardiac remodeling and heart failure. These results provide new insight into the molecular mechanisms of mtDNA sensing by the innate immune system and reveal that ZBP1 is a cooperative partner for cGAS. Moreover, our findings highlight ZBP1 as a potential therapeutic target in heart failure and other disorders where mtDNA instability drives disease-promoting IFN-I and inflammatory responses.

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Section: Resultsmentioning

confidence: 99%

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Lei

VanPortfliet

Chen

et al. 2022

Preprint

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“…ZBP1 recognizes Z-RNA in macrophages to activate the NLRP3 inflammasome and PANoptosis, an inflammatory programmed cell death pathway regulated by the PANoptosome complex with pyroptosis, apoptosis, and/or necroptosis key features of apoptosis 38 . Growing evidence suggests that ZBP1-mediated necroptosis is involved in antitumor immunity and tumorigenesis 39 . Yang et al 39 revealed that ZBP1-MLKL necroptotic signaling potentiated radiation-induced antitumor immunity via intratumoral STING pathway activation.…”

Section: Discussionmentioning

confidence: 99%

“…Growing evidence suggests that ZBP1-mediated necroptosis is involved in antitumor immunity and tumorigenesis 39 . Yang et al 39 revealed that ZBP1-MLKL necroptotic signaling potentiated radiation-induced antitumor immunity via intratumoral STING pathway activation. In a breast cancer study, ZBP1 expression is dramatically upregulated in necrotic tumors.…”

Section: Discussionmentioning

confidence: 99%

Necroptosis-associated classification combined with tumor microenvironment characteristic analysis of cutaneous melanoma

Jiang

et al. 2022

Sci Rep

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Necroptosis is a mode of programmed cell death that overcomes apoptotic resistance. The accurate prognosis of cutaneous melanoma is complicated to predict due to tumor heterogeneity. Necroptosis contributes to the regulation of oncogenesis and cancer immunity. We comprehensively investigated different necroptosis patterns by the non-negative matrix factorization (NMF) clustering analysis and explored the relationships among necroptosis patterns, infiltered immune cells, and tumor microenvironment (TME) scores. Two different necroptosis patterns were identified, and the two clusters could predict prognosis and immune landscape. A four-gene signature was successfully constructed and validated its predictive capability of overall survival (OS) in cutaneous melanoma patients. The prognostic value of the signature was further enhanced by incorporating other independent prognostic factors such as age and clinicopathological stages in a nomogram-based prediction model. Patients with lower risk scores tended to have better OS, higher TME score, immune checkpoints, immunophenoscore (IPS), and lower Tumor Immune Dysfunction and Exclusion (TIDE), which indicated better responses to immunotherapy. In addition, the pigmentation score of the high-risk group was visibly higher than those of the low-risk group. In conclusion, the necroptosis-related signature indicated favorable predictive performance in cutaneous melanoma patients, which provides guidance for immunotherapy and provide novel insights into precision medicine.

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“…In addition, authors believed that necroptotic tumor cells serve as potent immunizers in a prophylactic tumor vaccination model, which is an essential step in confirming that the cell death type is immunogenic ( Galluzzi et al, 2017 ). Furthermore, genes involved in type I IFN response were substantially enriched in necroptotic molecules-sufficient tumor cells, whereas necroptotic molecules absence limited the induction of type I IFN response–relevant genes in tumor cells ( Yang Y. et al, 2021 ), and type I IFNs have been certified to play a critical role in the functions of antitumor and immunity ( Demaria et al, 2019 ). This illustrated that necroptotic molecules will trigger type I IFN responses and remold the tumor microenvironment (TME).…”

Section: Discussionmentioning

confidence: 99%

Necroptosis is Related to Anti-PD-1 Treatment Response and Influences the Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma

Wang

Wang²,

Zhao³

et al. 2022

Front. Genet.

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The latest research suggesting that necroptosis plays a vital role in immune response. However, the influence of necroptosis on tumor microenvironment (TME) remodeling and immunotherapy is still unclear. We analyzed the variations in the expression of 26 necroptosis-related molecules in HNSCC and the influence of genome changes. We investigated HNSCC samples and determined that there are two necroptosis phenotypes in HNSCC cancer, and there are significant differences in cell infiltration characteristics and survival in different necroptosis phenotypes. We used the single‐sample gene set enrichment analysis to measure the level of necroptosis in patients with NecroticScore, we confirmed that the NecroticScore can predict the prognosis of HNSCC patients and the response to immunotherapy. Patients with a high NecroticScore are more sensitive to immunotherapy and have a better prognosis. Our study suggests a significant correlation between the expression imbalance of necroptosis-related molecules and suggests necroptosis plays an important role in modeling the TME. In addition, we construct a risk prediction model which could stratify patients with HNSCC and predict patient prognosis according to this necroptosis-related molecules. In conclusion, evaluating necroptosis modification patterns contributes to enhancing our understanding of TME and can guide more effective immunotherapy strategies.

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ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation

Abstract: ZBP1-MLKL necroptotic signaling bridges tumor cell damage to antitumor immune responses after radiation.

Cited by 99 publications

References 47 publications

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity

Necroptosis-associated classification combined with tumor microenvironment characteristic analysis of cutaneous melanoma

Necroptosis is Related to Anti-PD-1 Treatment Response and Influences the Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma

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