JOURNAL OF HAZARDOUS MATERIALS
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2025
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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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DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
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IF 9.7
Qingdong Li,Yuanyuan Cui,Zhenhong Xia,Wenjuan Gao,Jianmin Xiao,Zhen Zhao,Lei Yang,Guilong Zhang,Zhengyan Wu
Immunotherapy has emerged as a promising approach for melanoma treatment. However, the efficacy of traditional immune checkpoint inhibitors (ICIs) remains limited due to the immunosuppressive tumor microenvironment. In this study, a novel nano-immune agonist, pLCGM-OVA, was developed to induce cuproptosis and activate the cGAS-STING pathway, thereby enhancing melanoma immunotherapy. The pLCGM-OVA was synthesized by conjugating PDGFB with liposomes that encapsulate CuGdMn nanoclusters (CGM) and ovalbumin (OVA). Upon exposure to the acidic microenvironment of tumours, pLCGM-OVA undergoes degradation, releasing Cu ions, Mn ions, and free OVA. This release triggers reactive oxygen species-mediated cuproptosis and activates the cGAS-STING pathway via Mn, leading to the subsequent induction of immunogenic cell death (ICD). Simultaneously, free OVA and ICD antigens are presented to dendritic cells (DCs), promoting their maturation and enhancing cytotoxic T lymphocyte infiltration, thus improving the efficacy of tumour immunotherapy. In vitro and in vivo studies demonstrated that pLCGM-OVA significantly inhibited tumour growth and recurrence with minimal systemic toxicity, owing to the combined effects of cuproptosis and immunotherapy. Moreover, pLCGM-OVA exhibited excellent T 1 contrast (9.26 mM −1 s −1 ), significantly enhancing T 1 -weighted magnetic resonance imaging signals of tumours, facilitating accurate melanoma diagnosis. Overall, this work presents a highly promising candidate for the development of potent immune agonists for melanoma treatment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
·
IF 12.2
Li Mou,Daguang Sun,Jiayuan Qu,Xiaoyin Tan,Suli Wang,Qiang Zeng,Changjiang Liu
Iodoacetic acid (IAA) is an emerging unregulated iodinated disinfection byproduct with high toxicity and widespread exposure. IAA has potential reproductive toxicity and could damage male reproduction. However, the underlying mechanisms and toxicological targets of IAA on male reproductive impairment are still unclear, and thus Sprague-Dawley rats and Leydig cells were used in this work to decode these pending concerns. Results showed that after IAA exposure, the histomorphology and ultrastructure of rat testes were abnormally changed, numbers of Leydig cells were reduced, the hypothalamic-pituitary-testis (HPT) axis was disordered, and testosterone biosynthesis was inhibited. Proteomics analyses displayed that oxidative stress, endoplasmic reticulum stress, and steroid hormone biosynthesis were involved in IAA-caused reproductive injury. Antioxidant enzymes were depleted, while levels of ROS, MDA, 8-OHdG, and γ-H2A.X were increased by IAA. IAA triggered oxidative stress and DNA damage, and then activated the GRP78/IRE1/XBP1s and cGAS/STING/NF-κB pathways in Leydig cells. The two signaling pathways constructed an interactive network by synergistically regulating the downstream transcription factor CHOP, which in turn directly bound to and negatively modulated steroidogenic StAR, finally refraining testosterone biosynthesis in Leydig cells. Collectively, IAA as a reproductive toxicant has anti-androgenic effects, and the GRP78/IRE1 and cGAS/STING pathway crosstalk through CHOP facilitates IAA-mediated testosterone decline.
研究领域:
生殖毒理学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2025
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IF 9.6
Xiaoyu Pan,Yan Lin,Chunlin Lin,Songyi Liu,Penghang Lin,Xiang Lin,Ruofan He,ZiChen Ye,Jianxin Ye,Guangwei Zhu
The cGAS-STING signaling pathway is a pivotal immune response mechanism that bridges tumor and immune cell interactions. This study describes a multifunctional LPDAM nanoplatform integrating Lapachone, polydopamine (PDA), and Mn 2+ , which synergistically kills tumor cells and activates the cGAS-STING pathway, thereby inducing DC maturation and T cell activation to achieve potent antitumor immunity. In the tumor microenvironment, Lapachone generates H 2 O 2 via the NAD(P)H:quinone oxidoreductase 1 (NQO1 enzyme), while Mn 2+ catalyze H 2 O 2 conversion into •OH through chemodynamic effects (CDT). The photothermal effects (PTT) of PDA further amplify this cascade reaction, producing reactive oxygen species (ROS) that damage tumor mitochondria and release mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING pathway, while Mn 2+ enhances the sensitivity of cGAS to mtDNA, leading to robust antitumor immunity. Concurrently, photothermal-induced immunogenic cell death (ICD) promotes d endritic cells ( DCs) maturation, further strengthening immune responses. Moreover, Mn 2 ⁺ also serves as a contrast agent for T1-weighted magnetic resonance imaging (MRI), offering precise tumor visualization. This study demonstrates that the LPDAM nanoplatform facilitates Lapachone/CDT/PTT synergistic therapy under MRI guidance, showcasing its potential as an innovative strategy for combined immunotherapy in clinical oncology.
研究领域:
肿瘤学
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免疫学
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纳米医学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Translational Medicine
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2024
·Vol. 22
·期 1
·1-16
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IF 6.1
Xiong Yi,Chen Jiawen,Liang Wei,Li Kun,Huang Yingqi,Song Jingwen,Zhang Baoyu,Qiu Xiusheng,Qiu Dongbo,Zhang Qi,Qin Yunfei
Background Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated. Methods Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models. Results Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization. Conclusions The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.
研究领域:
免疫学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2024
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IF 2.7
Xiaodong Liu,Tianyi Jiang,Huiyun Jin,Chenxi Yan,Yuqi Tong,Jiaquan Ding,Yaqi Li,Lian Huang,Zhaohui Zhang
Beryllium sulfate (BeSO 4 ) can cause inflammation through the mechanism, which has not been elucidated. Mitochondrial DNA (mtDNA) is a key contributor of inflammation. With mitochondrial damage, released mtDNA can bind to specific receptors (e.g., cGAS) and then activate related pathway to promote inflammatory responses. To investigate the mechanism of mtDNA in BeSO 4 -induced inflammatory response in 16HBE cells, we established the BeSO 4 -induced 16HBE cell inflammation model and the ethidium bromide (EB)-induced ρ 0 16HBE cell model to detect the mtDNA content, oxidative stress-related markers, mitochondrial membrane potential, the expression of the cGAS-STING pathway, and inflammation-related factors. Our results showed that BeSO 4 caused oxidative stress, decline of mitochondrial membrane potential, and the release of mtDNA into the cytoplasm of 16HBE cells. In addition, BeSO 4 induced inflammation in 16HBE cells by activating the cGAS-STING pathway. Furthermore, mtDNA deletion inhibited the expression of cGAS-STING pathway, IL-10, TNF-α, and IFN-β. This study revealed a novel mechanism of BeSO 4 -induced inflammation in 16HBE cells, which contributes to the understanding of the molecular mechanism of beryllium and its compounds-induced toxicity.
研究领域:
毒理学
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细胞生物学
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免疫学
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Mengna Dong,Chan Xue,Xinhui Yang,Hongfang Liu,Hong Wang,Yonggui Liao,Yajiang Yang,Xiangliang Yang,Qin Wang
cGAS-STING pathway, an important innate immune signaling pathway, has attracted extensive attention in anti-tumor immunotherapy research. However, the limited delivery ratio of STING agonists and lactate-induced lactylation present significant challenges in advancing cGAS-STING antitumor immune response. Herein, natural anaerobic sulfate-reducing bacteria (SRB) are utilized as a biofactory to in situ biosynthesize MnS nanoparticles (MnS@SRB) for amplifying MnS-activated cGAS-STING anti-tumor immune responses through continuous lactate depletion by SRB. After intravenous injection, MnS@SRB can actively migrate to tumor tissues via SRB-mediated hypoxia targeting, further continually release H 2 S and Mn 2+ in the acidic tumor microenvironment. H 2 S stimulates mitochondrial dysfunction and induces mitochondrial DNA leakage, which is then recognized by cGAS to activate STING signaling pathway. Mn 2+ further augments STING-mediated secretion of type I interferons and inflammatory factors. Importantly, MnS@SRB can effectively metabolize lactate in tumors, thereby alleviating cGAS lactylation for amplifying cGAS-STING immune response and regulating macrophage phenotype to M1-type, reducing the tumor-infiltrating regulatory T cells and increasing CD8 + T cells level, further enhancing both adaptive and innate immunosurveillance. As a result, MnS@SRB effectively inhibite the tumors growth and metastasis. Therefore, MnS@SRB-based delivery system enables efficient cGAS activator delivery and tumor immunosuppressive microenvironment remodeling, thereby opening a new avenue for synergistically enhanced STING activation.
研究领域:
生物医学工程
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免疫学
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肿瘤学
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产品关联
DOI
高影响因子
EXPERIMENTAL AND MOLECULAR MEDICINE
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2025
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IF 12.9
Zhu Lijun,Tang Zhaohui,Jiang Wen,Dong Yuwen,Li Xiaofei,Huang Kai,Wu Tiancong,Xu Lingyan,Guo Wenjie,Gu Yanhong
Radiotherapy-induced DNA damage can lead to apoptotic cell death and trigger an anti-tumor immune response via the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway, which senses cytoplasmic double-stranded DNA. However, radiotherapy resistance poses a significant challenge in treating cancers, including colorectal cancer (CRC). Understanding the mechanisms underlying this resistance is crucial for developing effective therapies. Here we report that radiotherapy enhances cholesterol synthesis, which subsequently inhibits the cGAS–STING pathway, leading to radiotherapy resistance. Mechanistically, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) levels increase rapidly in response to radiation, resulting in increased cholesterol synthesis. This increased cholesterol sequesters STING in the endoplasmic reticulum, hindering its activation and downstream interferon signaling. Elevated HMGCR and cholesterol levels correlate with poor prognosis and reduced response to radiation therapy in patients with CRC. Importantly, pharmacological inactivation of HMGCR significantly enhanced radiotherapy responsiveness in animal models, dependent on cGAS–STING signaling-mediated anti-tumor responses. Our findings reveal that radiotherapy-induced cholesterol inhibits cGAS–STING signaling, facilitating tumor immune escape. Therefore, combining statins with radiotherapy represents a promising therapeutic strategy for treating CRC.
研究领域:
肿瘤学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-21
·
IF 12.6
Ma Shanshan,Zhang Xuequan,Zhu Xiaoqi,Yan Kangning,Wang Qin,Lei Lei,Li Jiasheng,Guo Jing,Tang Weizhong,Liu Junjie,Cao Jun,Wang Duo,Luo Tao
Manganese ions (Mn 2+ ) have emerged as promising activators of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, their clinical application was hindered by low bioavailability and limited immune activation pathways, which impaired their ability to trigger robust immune responses and achieve significant antitumor effects. To address these challenges, we developed a dual-modality immune nano-activator by coordinating manganese ions with quercetin. This strategy was designed to enhance the cGAS-STING pathway activation and elicit the immunogenic cell death, thereby strengthening the antitumor immune response. The engineered nano-activator demonstrated superior tumor-targeting ability and efficient cellular internalization. Upon exposure to near-infrared irradiation, the system harnessed photothermal effects to induce apoptosis in tumor cells while simultaneously accelerating the release of manganese ions and quercetin. The released manganese ions facilitated the generation of reactive oxygen species, which in conjunction with quercetin-induced apoptosis, amplified photothermal-induced DNA damage. This DNA damage further promoted the release of cytosolic DNA, which in turn activated the cGAS-STING pathway, thereby intensifying immune activation. Notably, the nano-activator also triggered immunogenic cell death, which synergized with the cGAS-STING activation to promote dendritic cell maturation and activate antigen-specific T-cell, significantly enhancing the immune response against the tumor. Both in vitro and in vivo studies confirmed that this nano-activator effectively inhibited tumor growth, with particularly pronounced effects when combined with anti-CTLA-4 antibodies. Graphical abstract
研究领域:
纳米医学
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肿瘤免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
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IF 9.6
Nan Zhong,Ziyue Zu,Yishi Lu,Xuan Sha,Yang Li,Yang Liu,Shangyu Lu,Xi Luo,Yan Zhou,Jun Tao,Feiyun Wu,Zhaogang Teng,Yuxia Tang,Shouju Wang
Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway could effectively initiate antitumor immunity in triple-negative breast cancer. However, current nuclear DNA-mediated activation of STING pathway remains constrained by the tight protection of nuclear membrane and histones, highlighting the need for new strategies to enhance its efficacy. Mitochondrial DNA (mtDNA), in contrast, is more vulnerable to damage. Herein, our nanoplatforms exploited the high glutathione (GSH) environment characteristic of tumors to release abundant Mn 2+ , which induced mitochondrial dysfunction and the release of endogenous mtDNA. The released mtDNA, in conjunction with Mn 2+ itself functioning as a strong cGAS agonist, effectively activated cGAS-STING pathway. Consequently, the cGAS-STING-dependent secretion of type I interferon successively enhanced the maturation of dendritic cells and cross-priming of CD8 + T cells. In a poorly immunogenic 4T1 tumor model, TPP-MMONs efficiently primed systemic antitumor immunity and significantly enhanced the therapeutic efficacy of αPD-L1 therapy, suppressing tumor growth in both localized and metastatic tumor models. These findings provided an innovative and straightforward strategy to enhance TNBC immunogenicity by targeting mitochondrial damage to induce mtDNA-mediated cGAS-STING activation, thereby sensitizing tumors to immune checkpoint inhibitor therapy. Statement of Significance The cGAS-STING pathway is a promising target for overcoming immunoresistance in TNBC. However, current nuclear DNA-based activation strategies are limited by the tight protection of nuclear membrane and histones. Herein, we reported novel manganese-rich, mitochondria-targeting nanoplatforms (TPP-MMONs), which can release abundant Mn²⁺ and significantly induce mitochondrial dysfunction, leading to the release of mtDNA. As a result, the nanoplatforms can effectively stimulate the cGAS-STING pathway, thereby enhancing immune responses and improving the therapeutic efficacy of αPD-L1 therapy, offering new insights into TNBC treatments.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
CANCER CELL
·
2023
·
IF 50.3
Lan Fang,Yun Hao,Haihong Yu,Xuemei Gu,Qiao Peng,Huimin Zhuo,Yaxu Li,Zhiyuan Liu,Jia Wang,Yunfei Chen,Jiawen Zhang,Hongling Tian,Yaohui Gao,Renyuan Gao,Hongqi Teng,Zezhi Shan,Jiali Zhu,Zhiqiang Li,Yu'e Liu,Yiyi Zhang,Fei Yu,Zhang Lin,Yujun Hao,Xin Ge,Jian Yuan,Hong-Gang Hu,Yanlei Ma,Huan-Long Qin,Ping Wang
Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.
研究领域:
免疫学
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肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
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IF 12.6
Xinyao Hu,Hua Zhu,Yang Shen,Lang Rao,Jiayi Li,Xiaoqin He,Ximing Xu
Tumor immunotherapy aims to harness the immune system to identify and eliminate cancer cells. However, its full potential is hindered by the immunosuppressive nature of tumors. Radiotherapy remains a key treatment modality for local tumor control and immunomodulation within the tumor microenvironment. Yet, the efficacy of radiotherapy is often limited by tumor radiosensitivity, and traditional radiosensitizers have shown limited effectiveness in hepatocellular carcinoma (HCC). To address these challenges, we developed a novel multifunctional nanoparticle system, ZIF-8@MnCO@DOX (ZMD), designed to enhance drug delivery to tumor tissues. In the tumor microenvironment, Zn²⁺ and Mn²⁺ ions released from ZMD participate in a Fenton-like reaction, generating reactive oxygen species (ROS) that promote tumor cell death and improve radiosensitivity. Additionally, the release of doxorubicin (DOX)-an anthracycline chemotherapeutic agent-induces DNA damage and apoptosis in cancer cells. The combined action of metal ions and double-stranded DNA (dsDNA) from damaged tumor cells synergistically activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, thereby initiating a robust anti-tumor immune response. Both in vitro and in vivo experiments demonstrated that ZMD effectively activates the cGAS-STING pathway, promotes anti-tumor immune responses, and exerts a potent tumor-killing effect in combination with radiotherapy, leading to regression of both primary tumors and distant metastases. Our work provides a straightforward, safe, and effective strategy for combining immunotherapy with radiotherapy to treat advanced cancer.
研究领域:
肿瘤学
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免疫学
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放射生物学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
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