Journal of Materials Chemistry B
·
2023
·
IF 7
Qi Long,Yuliang Yang,Fangling Liao,Haoting Chen,Dongyue He,Shengliang Li,Li Pengcheng,Weisheng Guo,Yafang Xiao
Photothermal immunotherapy has shown great potential for efficient cancer treatment. However, the immunosuppressive tumor microenvironment forms a heavy barrier for photothermal-induced anti-tumor immunity by inhibiting dendritic cells (DCs) maturation and cytotoxic T cell response. Moreover, the lack of reliable spatiotemporal imaging modalities makes photothermal immunotherapy difficult to guide tumor ablation and monitor the therapeutic outcomes in real time. Herein, we designed a theranostic thermosensitive liposome (PLDD) as a versatile nanoplatform to boost adaptive anti-tumor immunity of photothermal immunotherapy and achieve multiple bioimaging modalities in a real-time manner. The PLDD contains two major functional components: a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA). Upon irradiation, the heat generated by DTTB induced the immunogenic cell death (ICD) of the tumor and dissociated the structure of thermosensitive liposome to release DMXAA, which ultimately activated the STING pathway and promoted the ICD-induced immune response by increasing DC cells maturation and T cell recruitment. Meanwhile, the DTTB in PLDD displayed excellent second near-infrared (NIR-II) fluorescence and photoacoustic (PA) dual-modal imaging, which provided omnibearing information on the tumor and guided the subsequent therapeutic operation. Therefore, this versatile PLDD with light-triggered promotion of anti-tumor immunity and multiple spatiotemporal imaging profiles holds great potential for the future development of cancer immunotherapy.
研究领域:
生物医学工程
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癌症研究
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免疫治疗
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纳米技术
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诊疗学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Yuxuan Peng,Shuang Liang,Dan Liu,Kongshuo Ma,Kaiqing Yun,Mengli Zhou,Linna Hai,Mengdi Xu,Yiyang Chen,Zhaohui Wang
The highly immunosuppressive tumor microenvironment (TME) restricts the efficient activation of immune responses. To restore the surveillance of the immune system for robust activation, vast efforts are devoted to normalizing the TME. Here, a manganese-doped layered double hydroxide (Mn-LDH) is developed for potent anti-tumor immunity by reversing TME. Mn-LDH is synthesized via a one-step hydrothermal method. In addition to the inherent proton neutralization capacity of LDH, the introduction of manganese oxide endows LDH with an additional ability to produce oxygen. Mn-LDH effectively releases Mn 2+ and Mg 2+ upon exposure to TME with high levels of H + and H 2 O 2 , which activates synthase-stimulator of interferon genes pathway and maintains the cytotoxicity of CD8 + T cells respectively, achieving a cascade-like role in innate and adaptive immunity. The locally administered Mn-LDH facilitated a “hot” network consisting of mature dendritic cells, M1-phenotype macrophages, as well as cytotoxic and helper T cells, significantly inhibiting the growth of primary and distal tumors. Moreover, the photothermal conversion capacity of Mn-LDH sparks more robust therapeutic effects in large established tumor models with a single administration and irradiation. Overall, this study guides the rational design of TME-modulating immunotherapeutics for robust immune activation, providing a clinical candidate for next-generation cancer immunotherapy.
研究领域:
癌症免疫学
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纳米技术
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治疗开发
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免疫治疗
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肿瘤微环境
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Kaiyuan Liu,Pengfei Zan,Zihua Li,Hengli Lu,Peng Liu,Li Zhang,Hongsheng Wang,Xiaojun Ma,Feng Chen,Jing Zhao,Wei Sun
The immunosuppressive tumor microenvironment (ITME) of osteosarcoma (OS) poses a significant obstacle to the efficacy of existing immunotherapies. Despite the attempt of novel immune strategies such as immune checkpoint inhibitors and tumor vaccines, their effectiveness remains suboptimal due to the inherent difficulty in mitigating ITME simultaneously from both the tumor and immune system. The promotion of anti-tumor immunity through the induction of immunogenic cell death and activation of the cGAS-STING pathway has emerged as potential strategies to counter the ITME and stimulate systemic antitumor immune responses. Here we present a bimetallic polyphenol-based nanoplatform (Mn/Fe-Gallate nanoparticles coated with tumor cell membranes, MFG@TCM) which combines with mild photothermal therapy (PTT) for reversing ITME via simultaneously inducing pyroptosis in OS cells and activating the cGAS-STING pathway in dendritic cells (DCs). The immunostimulatory pathways, through the syngeneic effect, exerted a substantial positive impact on promoting the secretion of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, which favors remodeling the immune microenvironment. Consequently, effector T cells led to a notable systemic antitumor immune response, effectively inhibiting the growth of both primary and distant tumors. This study offers a comprehensive approach to treat OS by mild photothermal therapy and modulating the immune microenvironment, exhibiting considerable potential in addressing the constraints associated with current therapeutic modalities. This article is protected by copyright. All rights reserved
研究领域:
癌症治疗
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免疫学
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纳米技术
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
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IF 14
Jie Lei,Weifeng Zhang,Liang Ma,Yaqi He,Huaizhen Liang,Xiaoguang Zhang,Gaocai Li,Xiaobo Feng,Lei Tan,Cao Yang
The therapeutic effect of cancer immunotherapy is restrained by limited patient response rate caused by ‘cold’ tumors with an intrinsically immunosuppressive tumor microenvironment (TME). Activating stimulator of interferon genes (STING) confers promising antitumor immunity even in ‘cold’ tumors, but the further promotion of STING agonists is hindered by undesirable toxicity, low specificity and lack of controllability. Herein, an ultrasound-controllable cGAS-STING amplifying nanoagonist was constructed by coordinating mitochondria-targeting ligand triphenylphosphonium (TPP) to sonodynamic cobalt organic framework nanosheets (TPP@CoTCPP). The Co ions specifically amplify STING activation only when cytosolic mitochondrial DNA leakage is caused by sonocatalysis-induced ROS production and sensed by cGAS. A series of downstream innate immune proinflammatory responses induced by local cGAS-STING pathway activation under spatiotemporal ultrasound stimulation efficiently prime the antitumor T-cell response against bone metastatic tumor, a typical immunosuppressive tumor. We also found that the coordination of TPP augments the sonodynamic effect of CoTCPP nanosheets by reducing the band gap, improving O 2 adsorption and enhancing electron transfer. Overall, our study demonstrates that the targeted and amplified cGAS-STING activation in cancer cell controlled by spatiotemporal ultrasound irradiation boosts high-efficiency sonodynamic-ionicimmunotherapy against immunosuppressive tumor.
研究领域:
癌症免疫疗法
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纳米技术
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生物医学工程
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分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
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2022
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IF 4.631
Renhui Huang,Qi Shi,Shutian Zhang,Hong Lin,Chengzhi Han,Xinyi Qian,Yijun Huang,Xiaorong Ren,Jiayuan Sun,Nana Feng,Chunmei Xia,Meng Shi
Purpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS.Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system.Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats.Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.
研究领域:
免疫学
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病理生理学
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呼吸医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
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IF 16
Xiangling Zhang,Dongsheng Tang,Haihua Xiao,Bin Li,Kun Shang,Dan Zhao
Recent research has demonstrated that activating the cGAS-STING pathway can enhance interferon production and the activation of T cells. A manganese complex, called TPA-Mn, was developed in this context. The reactive oxygen species (ROS)-sensitive nanoparticles (NPMn) loaded with TPA-Mn are developed. NPMn activates the cGAS-STING pathway via cGAS activation (i.e., 1.6-fold enhancement of P-STING), which in turn increases the secretion of pro-inflammatory cytokines (e.g., TNF-α, IL-6, and IL-2). This promotes dendritic cell maturation, enhances the infiltration of cytotoxic T lymphocytes, and reduces the percentage of immunosuppressive regulatory T cells. In addition, it is crucial to emphasize that cisplatin-induced DNA damage can potentially trigger activation of the cGAS-STING pathway. NPMn, in combination with low-dose NPPt, a carrier of a Cis(IV) prodrug capable of causing DNA damage, augments the cGAS-STING pathway activation and significantly activates the tumor immune microenvironment (TIME). Furthermore, combined with anti-PD-1 antibody, NPPt+NPMn shows synergistic efficacy in both ovarian cancer peritoneal metastases and recurrence models. It not only effectively eliminates tumors but also induces a strong immune memory response, providing a promising strategy for the clinical management of ovarian cancer. This work offers a design of manganese-based nanoparticles for immunotherapy.
研究领域:
肿瘤学
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免疫学
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纳米技术
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-20
·
IF 10.6
Zhang Xiaodian,Tian Hailong,Chen Yang,Liang Baichuan,Nice Edouard C.,Huang Canhua,Xie Na,Zheng Shaojiang
Immunotherapy has shown marked progress in promoting systemic anti-colorectal cancer (CRC) clinical effects. For further effectively sensitizing CRC to immunotherapy, we have engineered a pH-sensitive zeolitic imidazolate framework-8 (CS/NPs), capable of efficient cGAS-STING pathway activation and immune checkpoint blockade, by encapsulating the chemotherapeutic mitoxantrone (MTX) and immunomodulator thymus pentapeptide (TP5) and tailoring with tumor-targeting chondroitin sulfate (CS). In this nanoframework, CS endows CS/NPs with specific tumor-targeting activity and reduced systemic toxicity. Of note, the coordinated Zn2+ disrupts glycolytic processes and downregulates the expression of glucose transporter type 1 (GLUT1), thus depriving the cancer cells of their energy. Zn2+ further initiates the adenosine 5’-monophosphate activated protein kinase (AMPK) pathway, which leads to PD-L1 protein degradation and sensitizes CRC cells to immunotherapy. Moreover, the damaged double-stranded DNA during MTX treatment activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which works together with TP5 induced the proliferation and differentiation of T lymphocytes and dendritic cells to further enhance the anti-CRC immune response. Therefore, CS/NPs efficiently sensitize cells to chemotherapy and stimulate systemic antitumor immune responses both in vitro and in vivo, representing a promising strategy to increase the feasibility of CRC immunotherapy.Graphical Abstract
研究领域:
纳米技术
·
癌症免疫治疗
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分子生物学
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药学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yanmei Li,Junmei Nie,Xinyu Li,Ni Yan,Renjiang Kong,Jiaqi Huang,Yeyang Wu,Zhuofeng Li,Yingtao Zhong,Xin Chen,Hong Cheng
Stimulator of interferon genes (STING) plays an essential role in initiating the innate anti-tumor immunity, which could be activated by the cytosolic DNA but suppressed by the immunosuppressive cells. In this work, a self-delivery ternary immunostimulant (designated as ImmSt) is fabricated for colorectal cancer therapy with the immunological cascades of photodynamic DNA damage and T regulatory cell inhibition. Among which, the photosensitizer of Chlorin e6 (Ce6), the STING agonist of 5,6-dimethylxanthine-4-acetic acid (DMXAA) and the phosphatidylinositol 3-kinases (PI3Ks) inhibitor of ZSTK474 could self-assemble into uniform nanomedicine without drug excipient, which enhances the drug stability, bioavailability and pharmacological activities. Importantly, the photodynamic therapy (PDT) effect of ImmSt produces enormous reactive oxygen species to ablate tumor cells, and also triggers the release of cytosolic DNA to amplify the STING signal in combination with the STING agonist. Moreover, ImmSt is able to induce a systemic anti-tumor immunity by the cascade activation of T cells and the decrease of T regulatory cells. In vitro and in vivo results confirm that ImmSt can efficiently eradicate colorectal cancer without severe side effects, which may provide a sophisticated mechanism for immunotherapy in consideration of the immune activation and immunosuppressive factors.
研究领域:
肿瘤学
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免疫疗法
·
药理学
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纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Journal of Hepatocellular Carcinoma
·
2025
·
IF 3.4
Jiayuan Zhang,Tian Tian,Shanshan Tian,Jinhai Yao,Yingwan Zhang,Rujia Xie,Ting Yang,Bing Han
Purpose This study aims to investigate the mechanism of action of arsenic-based agents against hepatocellular carcinoma (HCC) and to identify effective drug targets for HCC treatment.Methods Huh7 and HepG2 cells treated with NaAsO2 were assessed for cell viability, pyroptosis, migration, and invasion after undergoing lentiviral transfection. An orthotopic liver tumor model was established and divided into a model group and a treatment group. Proteins associated with QRICH1, PRMT1, cGAS-STING, and the classical pyroptosis pathway were quantified using Western blotting. The intracellular expression and localization of PRMT1 and NLRP3 in HCC were analyzed through cellular immunofluorescence. Co-immunoprecipitation (Co-IP) was performed to examine the protein interactions between PRMT1 and cGAS, as well as between STING and NLRP3. Chromatin immunoprecipitation (ChIP) was used to confirm QRICH1 enrichment in the PRMT1 promoter region.Results NaAsO2 treatment significantly inhibited the proliferation of Huh7 and HepG2 cells and effectively blocked their migration and invasion capabilities, while promoting cellular pyroptosis. Quantitative polymerase chain reaction(QRCR) and ChIP assays confirmed that NaAsO2 regulates PRMT1 expression by down-regulate QRICH1 binding in the PRMT1 promoter region. Additionally, NaAsO2 decreased the expression of the QRICH1-PRMT1 complex and upregulated the cGAS-STING signaling pathway, activating the downstream NLRP3-dependent classical pyroptosis pathway. Overexpression of QRICH1 reversed these effects.Conclusion NaAsO2 inhibits the expression of the QRICH1-PRMT1 axis, activates cGAS-STING signaling pathway transduction, and induces pyroptosis in HCC cells, thereby increasing the infiltration of immune cells in liver cancer tissues.
研究领域:
分子生物学
·
肿瘤学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Huanhuan Liu,Yuan Sun,Jindian Li,Yingxi Chen,Jia Liu,Jianyang Fang,Hongzhang Yang,Lixia Feng,Shilan Peng,Rongqiang Zhuang,Zhide Guo,Xianzhong Zhang
The stimulator of interferon genes (STING) is a pivotal protein in the production of STING-dependent type I interferon, which has the potential to enhance tumor rejection. The visualization of STING in the tumor microenvironment is valuable for STING-related treatments, but few STING imaging probes have been reported to date. In this study, we developed a novel 18F-labeled agent ([18F]F-CRI1) with an acridone core structure for the positron emission tomography (PET) imaging of STING in CT26 tumors. The probe was successfully prepared with a nanomolar STING binding affinity of Kd = 40.62 nM. [18F]F-CRI1 accumulated quickly in the tumor sites and its uptake reached a maximum of 3.02 ± 0.42% ID/g after 1 h i.v. injection. The specificity of [18F]F-CRI1 was confirmed both in in vitro cell uptake and in vivo PET imaging by blocking studies. Our findings suggest that [18F]F-CRI1 may be a potential agent for visualizing STING in the tumor microenvironment.
研究领域:
癌症研究
·
分子成像
·
核医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 13.2
Yanming Xia,Lixin Hu,Xiaohu Wang,Mingxi Li,Bo Shi,Siqi Zhu,Yutong Wu,Shuting Xiang,Lifang Yin,Suxin Li
Stimulator of interferon genes (STING) is a promising therapeutic target against cancer by bridging the innate and adaptive immunity. However, STING-based monotherapy shows compromised efficacy and dose-limited toxicity in early-stage clinical trials. Here we reveal that indoleamine 2, 3-dioxygenase 1 (IDO1) serves as an inherent negative regulator of STING signaling in dendritic cells to restrain antitumor immune responses. Besides as a consequence of STING signaling that contributes to immune suppression, IDO1 concurrently suppresses STING activity via its metabolites, thus establishing a negative feedback loop. Building on this insight, we develop a two-in-one nanosystem (SIANP) perturbing this inhibitory machinery to amplify STING-mediated antitumor activity. SIANP accumulates at tumor tissues, displays tropism toward dendritic cells in vivo , and facilitates cytosolic co-delivery of STING agonist and IDO1 siRNA at single-cell level, leading to elevated antigen presentation and CD8 + T cell priming with reduced T cell exhaustion or toxicity. This coordination suppresses tumor growth and prolongs survival in multiple established, metastatic, and recurrent tumor models. Remarkably, blockade of IDO1 by SIANP significantly amplifies STING signaling in resected human patient tissues. This work presents a robust nanoengineering approach to overcome immune tolerance arising from negative feedback loops for advanced cancer immunotherapy.
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产品关联
DOI
高影响因子
Cell Chemical Biology
·
2026
·
IF 9
Qingxuan Chen,Ancheng Shen,Xinyi Shi,Tailiang Lin,Qinghua Wang,Zhen Wang,Xuekui Yu,Buyong Ma,Chunyong Ding,Ao Zhang
Overactive stimulator of interferon gene (STING) signaling drives inflammatory and autoimmune diseases, making STING inhibition a promising therapeutic strategy. However, the complex binding mechanisms and limited structural diversity hinder the development of STING inhibitors. In this study, we identified a small-molecule STING inhibitor, Y-320, via cell-based screening. It binds STING with nanomolar affinity and potently inhibits STING-mediated interferon signaling in human and mouse cells. Mechanistically, Y-320 blocks the Golgi translocation and phosphorylation of STING, preventing interferon regulatory factor 3 (IRF3) recruitment. Notably, Y-320 allosterically targets the non-canonical transmembrane domain (TMD) pocket without competing with the endogenous agonist 2′3′-cGAMP by engaging residues Y46 and W119 in the transmembrane helices 2 and 4. Importantly, Y-320 alleviated cisplatin-induced acute kidney injury in mice in a STING-dependent manner. This work not only reveals an additional mechanism underlying the regulatory complexity of STING but also provides a TMD-targeted allosteric STING inhibitor with demonstrated efficacy in both in vitro and in vivo models.
✓ 已验证
DOI
PubMed
高影响因子
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