JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Yanming Xia,Bo Shi,Keke Wang,Lixin Hu,Qiran Wang,Shuxian Xu,Xiaohu Wang,Pengcheng Xu,Yuanbin She,Haitang Xie,Suxin Li,Lifang Yin
The cGAS-STING axis is a promising therapeutic target against cancer. However, most activators require STING signaling in the host, especially within antigen-presenting cells, which are rare in a cold tumor microenvironment. The cGAS-STING cascade is also present within cancer cells but with suppressed activity. Such a paradoxical situation may account for the clinical failures. Herein, we develop a trinity STING-activating nanoparticle (CMTP) coordinated with cGAMP, Mn 3+ , and porphyrin to awaken autologous STING signaling in cancer cells. CMTP disintegrates into Mn 2+ and TCPP upon elevated glutathione in cancer cells, where TCPP triggers mitochondrial DNA leakage, enhancing cGAS enzymatic activity in coordination with Mn 2+ , while concurrent cGAMP release from framework synergizes to amply STING activity. Consequently, CMTP exploits cancer cells as reservoirs for cGAS-STING signaling to promote DC maturation and T cell priming. A single administration of CMTP demonstrates robust efficacy in both hot MC38 and cold 4 T1 murine tumors. Genetic knockout studies confirm that STING in cancer cells, rather than in the host, is critical for antitumor performance. The feasibility of immune modulation is further validated in resected human patient tissues. This work presents a potent STING-activating nanomedicine based on coordination chemistry and underscores the potential of harnessing cancer cells' autologous cGAS-STING machinery in immunotherapy.
研究领域:
肿瘤学
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免疫学
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药剂学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Lu Liu,Zhongxia Wang,Yulin Qi,Ang Huang,Caiping He,Xiaoyan Zhan,Xiaohe Xiao,Zhaofang Bai
Aberrant activation of the cGAS-STING pathway has been implicated in the pathogenesis of diverse inflammatory diseases. Kurarinone, a flavonoid compound isolated from Sophorae tonkinensis Radix et Rhizoma, has been reported to exhibit anti-inflammatory effects and is used to treat inflammatory diseases. But the effect of kurarinone on the cGAS-STING pathway has not been well studied. We aimed to investigate the impact of Kurarinone on cGAS-STING pathway activation and its protective effect against cGAS-STING-mediated inflammatory diseases. BMDMs and THP-1 cells pretreated with Kurarinone or vehicle were stimulated with ISD or various STING agonists; the protein level of p-IRF3 was analyzed by western blotting, and the secretion and mRNA level of inflammatory cytokines were detected by ELISA and qPCR, respectively. To further explore the potential targets and molecular mechanisms of Kurarinone, nucleocytoplasmic separation assays, STING oligomerization experiments, cellular thermal shift assays, drug affinity responsive target stability assays, and molecular docking were conducted. Additionally, DSS-induced inflammatory bowel disease and ConA-induced autoimmune hepatitis models were used to evaluate the effects of Kurarinone on cGAS-STING-mediated inflammatory diseases. In vitro, Kurarinone inhibited the phosphorylation of STING and IRF3, reduced IFNβ release, and downregulated the transcription of IFNβ, IL-1β, CXCL10, IL-6, TNF-α, and ISG15, in ISD-stimulated BMDMs and THP-1 cells. Additionally, Kurarinone suppressed IRF3 nuclear translocation, disrupted the interaction between STING and IRF3, but did not affect STING oligomerization. Furthermore, Kurarinone reduced the thermostability of STING while increasing its susceptibility to proteolytic degradation. The molecular docking results indicated a strong interaction between Kurarinone and STING. In vivo, Kurarinone attenuated the inflammatory response in DSS-induced inflammatory bowel disease and ConA-induced autoimmune hepatitis models by inhibiting cGAS-STING signaling activation. In conclusion, Kurarinone targets the STING protein to interfere with the interaction between IRF3 and STING, thereby inhibiting the activation of the cGAS-STING signaling pathway. Additionally, Kurarinone ameliorates inflammatory diseases by suppressing the cGAS-STING pathway. This study provides a potential candidate drug for the clinical treatment of STING-driven inflammatory diseases.
研究领域:
免疫学
·
分子生物学
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药理学
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生物化学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Ru-Yang Zhao,Mu-Zi Li,Qi-Qian Wang,Fu-Wei Jiang,Yi Zhao,Jin-Long Li
Butachlor (BTR), a globally prevalent amide herbicide, poses significant environmental health risks due to its bioaccumulation potential and documented chronic toxicity in mammalian systems. Given the spleen's pivotal role in orchestrating systemic immune homeostasis, this study investigated BTR-induced immunopathological mechanisms in ICR mice following 28-day subacute exposure (10 mg/kg). Histopathological examination revealed significant disorganization of the splenic marginal zone architecture, concomitant with ultrastructural mitochondrial abnormalities and a reduction in mitochondrial membrane potential (ΔΨm). Mitochondrial permeability transition pore opening triggered cytoplasmic translocation of mitochondrial DNA (mtDNA), activating the stimulator of interferon genes (STING) pathway—a master regulator of innate immunity. STING activation initiated bifurcated downstream signaling, evidenced by TBK1 phosphorylation and subsequent IRF3 / NF-κB nuclear translocation. This dual signaling cascade simultaneously executed immunogenic cell death via Gasdermin D-dependent pyroptosis (cleaved GSDMD-NT) and drove macrophage polarization (IFN-α / β, IL-1β, TNF-α). Crucially, pharmacological STING inhibition with C-176 attenuated both pyroptosis (GSDMD cleavage reduced) and inflammatory cytokine surge. Our findings not only pioneer the identification of the mtDNA-STING axis as the central mechanism underlying BTR-induced splenic immunotoxicity but also validate STING inactivation as a targeted strategy to mitigate herbicide-associated immune dysfunction. This work provides critical insights for environmental toxicant risk assessment and immunomodulatory.
研究领域:
环境毒理学
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免疫学
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分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Science China-Life Sciences
·
2024
·
IF 8
Zhang Yinghui,Liu Yadan,Jiang Bing,Chen Lifan,Hu Jie,Niu Buying,Chang Jie,Fan Zisheng,Zhou Jingyi,Wang Yajie,Teng Dan,Ma Ning,Wang Xiaofeng,Yang Ruirui,Zheng Mingyue,Zhang Sulin
The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. The activation of STING is a multi-step process that includes binding with cGAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and inflammatory cytokines. It has been demonstrated that disruption of any of these steps can effectively inhibit STING activation. Traditional structure-based drug screening methodologies generally focus on specific binding sites. In this study, a TransformerCPI model based on protein primary sequences and independent of binding sites is employed to identify compounds capable of binding to the STING protein. The natural product Licochalcone D (LicoD) is identified as a potent and selective STING inhibitor. LicoD does not bind to the classical ligand-binding pocket; instead, it covalently modifies the Cys148 residue of STING. This modification inhibits STING oligomerization, consequently suppressing the recruitment of TBK1 and the nuclear translocation of IRF3 and NF-κB. LicoD treatment ameliorates the inflammatory phenotype in Trex1 −1− mice and inhibits the progression of DSS-induced colitis and AOM/DSS-induced colitis-associated colon cancer (CAC). In summary, this study reveals the potential of LicoD in treating STING-driven inflammatory diseases. It also demonstrates the utility of the TransformerCPI model in discovering allosteric compounds beyond the conventional binding pockets.
研究领域:
免疫学
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药理学
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分子生物学
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炎症
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药物发现
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Sheng Liu,Bo Yang,Yingxiang Hou,Kaige Cui,Xiaozhu Yang,Xiaoxiong Li,Lianwan Chen,Shichao Liu,Zhichao Zhang,Yuanyuan Jia,Yufeng Xie,Ying Xue,Xiaomei Li,Bingxue Yan,Changxin Wu,Wen Deng,Jianxun Qi,Defen Lu,George F. Gao,Peiyi Wang,Guijun Shang
Summary 2′,3′-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2′,3′-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.
研究领域:
免疫学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PLoS Pathogens
·
2023
·Vol. 19
·期 4
·e1011314
·
IF 6.7
Lin Lv,Li Chai,Jie Wang,Mengge Wang,Danhui Qin,Hui Song,Yue Fu,Chunyuan Zhao,Jihui Jia,Wei Zhao,Mutian Jia
Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo . Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases.
Selenoproteins are crucial for various physiological processes. Most selenoproteins locate in the cytoplasm and regulate redox pathways to protect cells from oxidative stress. However, the potential roles of transmembrane selenoproteins are largely unknown. Here, we identified Selenoprotein K (SELENOK), an ER-located transmembrane selenoprotein, as a physiological enhancer of STING-dependent antiviral innate immunity. SELENOK is upregulated during viral infection and enhances STING oligomerization to facilitate the activation of the cGAS-STING pathway and suppress viral replication. These results will be valuable for understanding the physiological roles of transmembrane selenoproteins in immunity. Furthermore, as aberrant STING activation has been linked to various pathological conditions, control of STING activity by SELENOK may be a prime therapeutic strategy.
研究领域:
免疫学
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病毒学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-21
·
IF 12.6
Yang Yi,Guo Jiaxin,Qi Jialong,Deng Wenxia,Hu Jialin,Hasan Muhammad Waqqas,Deng Fei,Zhou You,Song Zhengji,Deng Wei,Chen Wenjie
Immune checkpoint blockade therapy (iCBT) has revolutionized cancer treatment, however, there is a low response rate, especially in treating postsurgical reoccurring tumors. Vaccine based immunotherapy can sensitize iCBT, but its development was largely hindered by inefficient delivery and high requirements of storage. In this study, the vaccine loaded with immunostimulant was employed to improve iCBT-based adjuvant postsurgical therapy. A lyophilized, antigen E7 peptide and manganese ion (Mn 2+ ) co-delivered tumor vaccine was developed based on lipid nanoparticles (EM@LNP). The vaccination efficacy was examined in both prophylactic and therapeutic schemes in murine subcutaneous models, the synergetic effect of vaccination combined with anti-PD-1 therapy was further investigated in post-operative tumor model. EM@LNP vaccination elicited effective CD8 + T cell response through modulating tumor immunosuppressive microenvironment and conferring immune memory, demonstrating potent immunization in both preventive and therapeutic schemes. What’s more, EM@LNP vaccination orchestrated with iCBT, efficiently repressing tumor recurrence. Further mechanism studies using inhibitor for cells invitro and the investigation using STING −/− mice confirmed that the cGAS-STING signaling pathway activated by Mn 2+ is indispensable for LNP vaccination and the coordination with iCBT-based adjuvant immunotherapy. In summary, this study shows a lyophilized LNP vaccine could significantly amplify iCBT efficiency, providing a translational strategy of adjuvant immunotherapy for treating postsurgical tumor recurrence. Graphical abstract
研究领域:
肿瘤学
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免疫学
·
药剂学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Mengzi Hu,Yaqiong Wang,Xue-Bo Yin
In addition to the robust adhesive properties, there is a pressing demand for ideal adhesives in tumor surgery that possess anti-tumor therapeutic effects. In this study, we introduce BSA-MnO 2 -GP@Ca-Y (BMGY) bio-glue by integrating bovine serum albumin (BSA)-MnO 2 , genipin (GP), and Ca-Y zeolite. Ca-Y zeolite exhibits the thrombin activity for hemostasis, while the cross-linking of BSA, GP, and skin tissue induces wound adherence upon laser irradiation for normalized skin structure within nine days. The heat generated during the “photothermal suture” process ablates residual tumor cells and produces antigen fragments, which are internalized by antigen presenting cells. The released Mn ions subsequently activate the cGAS-STING pathway, enhancing immunogenicity. Consequently, tumor-infiltrating p-TBK1 and interferon-β levels are significantly increased, ensuring robust anti-tumor immunity following BMGY treatment. Thus, BMGY bio-glue achieves hemostasis, wound bonding, ablation of residual tumor cells, and tumor recurrence inhibition, simultaneously. Beyond Ca-Y zeolite, BSA-MnO 2 -GP serves as a versatile platform for loading other drugs or active species to boost therapeutic efficacy. Therefore, we present a successful bio-glue paradigm with significant translational potential for various postsurgical management applications.
研究领域:
生物医学工程
·
肿瘤免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Xueping Wei,Junsong Jing,Rongrong Huang,Ting Zhou,Lianhao Wu,Guoteng Ou,Youping Wu,Jingjin Hu,Wenwen Zhu,Yueguo Wu,Yuanyuan Li,Sheng Zhang,Zhenqiang You
Ethnopharmacological relevance Pulmonary fibrosis (PF) is an irreversible lung disease that severely affects human respiratory function. Traditionally, the natural plant Quzhou Fructus Arantii (QFA) has therapeutic effects on respiratory diseases. However, the effects and the mechanism of anti-fibrotic have not been elucidated. Aim of the study In this study, QFAE-nB was extracted from QFA, the aims of this study include understanding the correlation between Bleomycin (BLM)-induced PF and STING pathway in mice, as well as exploring the role and mechanisms of QFAE-nB in the treatment of PF. Materials and methods QFAE-nB was extracted from QFA, six main chemical components in QFAE-nB were identified by HPLC–QTOF–MS/MS, and quantitative analysis was conducted by HPLC. qPCR and Western blot were used to verify the molecular mechanism of QFAE-nB, and the anti-fibrotic effect of QFAE-nB was determined by hematoxylin-eosin (HE) staining and Masson staining as well as immunohistochemistry. TREX1-KO and STING-KO mice were used to verify the relationship between STING and PF and the important target action of QFAE-nB. Results Six main flavonoids in QFAE-nB were identified as eriocitrin (0.76%), neoeriocitrin (2.79%), narirutin (4.31%), naringin (35.41%), hesperidin (1.74%), and neohesperidin (27.18%). The results showed that BLM-induced PF was associated with its exacerbated release of proinflammatory factors and chemokines in lung tissues. In addition, QFAE-nB alleviated BLM-induced lung fibrosis in mice by inhibiting the activation of the STING signaling pathway and reducing the signal transduction of TBK1–IRF3 and TBK1–NF-κB pathways. Notably, knockout of the TREX1 gene caused massive inflammation and even induced PF in the lung tissues, whereas QFAE-nB effectively alleviated inflammation and reduced PF. The deletion of the STING gene suppressed BLM-induced PF and inflammation, but STING-KO mice treated with QFAE-nB showed even lower expression levels of proinflammatory factors and chemokine. Conclusions The STING pathway plays an important role in PF, and QFAE-nB alleviates PF by mainly targeting the inhibition of the STING pathway to reduce inflammation. Together, the study paves the way for targeting the STING pathway in PF treatment.
研究领域:
药理学
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民族药理学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Cell and Bioscience
·
2023
·Vol. 13
·期 1
·1-10
·
IF 7.5
Yu Yu,Wang Miao,Li Xiao-Wei,Mao Jie,Zhu Ying-Jie,Wang Na,Yin Le-Hua,Guo Zeng-Lin,Cai Hong,Li Tao,Liang Ting-Ting,Cui Jiuwei,Zhou Tao
Background Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is critical for cytosolic DNA-sensing and the subsequent immune responses. The inappropriate activation of this pathway leads to DNA-induced autoimmune response. Understanding the precise regulation of cGAS-STING pathway is important for developing therapeutics to treat several autoimmune diseases caused by self-DNA.Results We report that Meloxicam (MXC) inhibits intracellular DNA-, but not RNA-induced immune responses. We find that MXC inhibits the phosphorylation of STING by examining in different cells with various DNA stimulations. We further find that MXC significantly dampens the expression levels of interferon-stimulated genes (ISGs) by using DNA 3’ repair exonuclease 1 (TREX1)-deficient cell, an experimental model for self-DNA-induced autoimmune disease. Importantly, we demonstrate that MXC could promote the survival in Trex1–/– mouse model for Aicardi-Goutières syndrome (AGS).Conclusion sOur study identified a non-steroidal anti-inflammatory drug, MXC, that exhibits potential effect in treating the autoimmunity caused by self-DNA.
研究领域:
免疫学
·
药理学
·
自身免疫疾病
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产品关联
DOI
PubMed
高影响因子
NATURE IMMUNOLOGY
·
2020
·Vol. 21
·期 7
·727-735
·
IF 20.479
Jia Mutian,Qin Danhui,Zhao Chunyuan,Chai Li,Yu Zhongxia,Wang Wenwen,Tong Li,Lv Lin,Wang Yuanyuan,Rehwinkel Jan,Yu Jinming,Zhao Wei
Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS–STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress–induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.
研究领域:
免疫学
·
细胞生物学
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病毒学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Fei Wang,Shuhan Chen,Yinhe Xia,Caihong Liu,Zhou Xu,Ruilong Song,Wenfeng Liu,Tingting Liu,Gang Chen,Qingquan Liu
Influenza epidemics remain a global public health challenge. Vaccination with nucleic acid-based vaccines, which trigger strong cellular and humoral immune responses, represents a promising approach for preventing virus infection. However, its effectiveness relies on efficient delivery and an immunoadjuvant. Here, we constructed a gene- and nanoengineered vaccine delivery platform via modifying MnO2 nanoparticles (NPs) onto the surface of the M13 phage, which carried the hemagglutinin stem gene of influenza A virus preceded by a eukaryotic initial transcriptional region. Specifically, the M13 phage protected the inserted nucleic acid vaccine against degradation due to the existence of capsid proteins. MnO2 NPs released Mn2+ ions under the acidic condition of endolysosomes, thereby promoting the cytoplasmic delivery of phage vaccines, which significantly improved the antigen expression. Moreover, Mn2+ acted as a potent adjuvant for dendritic cell maturation by activating the cGAS/STING pathway. Immunization with the engineered phage vaccine induced CD4+ T cell, CD8+ T cell, and humoral immune responses in mice. In infected mouse models, the vaccines ameliorated weight loss, survival rate, lung virus titers, and pulmonary pathologies and conferred full protection against influenza viruses. Collectively, we developed a dual-engineered phage vaccine platform, offering an alternative regimen for optimizing nucleic acid vaccines, which may have broad applications in the rational design of vaccine formulations.
研究领域:
病毒学
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免疫学
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药学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）