ADVANCED FUNCTIONAL MATERIALS
·
2025
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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
·
2025
·
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
✓ 已验证
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Bin Liu,Xiaorui Chen,Yanlin Zhu,Hao Chen,Jia Tan,Zhuang Yang,Jing Li,Pan Zheng,Lili Feng,Qingqing Wang,Shili Gai,Lei Zhong,Piaoping Yang,Ziyong Cheng,Jun Lin
To improve the efficiency and application prospects of metal peroxides in tumor therapy, the synthesis of bimetallic peroxides via simple yet effective approaches will be highly significant. In this work, hyaluronic acid modified zinc-copper bimetallic peroxides (ZCPO@HA) nanoparticles are synthesized through a one-step symbiotic method by co-hydrolysis of zinc acetate and copper acetate in weakly alkaline solution, followed by modification with sodium hyaluronate. Upon decomposition in the tumor microenvironment, ZCPO@HA nanoparticles can generate a considerable content of hydroxyl radical (·OH) by Fenton-like reaction between Cu 2+ and self-compensating hydrogen peroxide, while downregulating the expression of glutathione peroxidase 4 to induce ferroptosis. The abundant release of Cu 2+ leads to the aggregation of dihydrolipoamide S-acetyltransferase and the reduction of iron-sulfur cluster proteins, causing cuproptosis. The immunogenic cell death of tumor cells releases abundant damage associated molecular patterns, effectively activating the adaptive immune response. Zn 2+ and ·OH cause mitochondrial damage, leading to the release of a substantial amount of mitochondrial DNA. This subsequently activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, enhancing the innate immune response. In conclusion, it synthesizes a new type of bimetallic peroxides by one-step symbiosis for activating anti-tumor immunotherapy combined with immune checkpoint inhibitor.
研究领域:
生物化学
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肿瘤学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2022
·
IF 5.016
Alan Xu,Ruoxi Yang,Mingfei Zhang,Xiang Wang,Yuxi Di,Baoping Jiang,Yongxiang Di,Zhanwei Zhou,Lingling Zhou
The abundant M1 macrophages in the joint synovium were the main factors that exacerbate rheumatoid arthritis (RA) by secreting various types of inflammatory cytokines. Here, we note that cGAS-STING, an important pro-inflammatory pathway, was significantly up-regulated in RA, enabling it be the potential target for RA therapy. Therefore, in this work, we developed M1 macrophages targeted micelles capable of cGAS-STING pathway inhibition for the smart treatment of RA. The folic acid (FA) and lauric acid (LA) were modified on dextran to obtain an amphiphilic polymer (FDL). Then, FDL was subsequently applied to encapsulate triptolide (TP) to form FDL@TP nanomicelles. The FDL@TP could target the joint and enhance the cell uptake of TP by M1 macrophages (overexpressing folate receptor-β), which also reduced the side effects of TP on normal tissues. In M1 macrophages, the released TP, acted as an anti-inflammatory and immunosuppressant, obviously down-regulated the expressions of cGAS and STING protein, and thus reduced the secretion of TNF-α, IL-1β and IL-6. Importantly, compared with the same dose of free TP, FDL@TP could significantly enhance the anti-inflammatory effect. Therefore, FDL@TP nanomicelles were believed to be superior candidates for the clinical treatment of RA.
研究领域:
药理学
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免疫学
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纳米技术
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风湿病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Lei Cao,Huixiang Tian,Man Fang,Zhe Xu,Dongsheng Tang,Juan Chen,Jiye Yin,Haihua Xiao,Kun Shang,Hongbin Han,Xiangping Li
cGAS-STING pathway, as an essential intracellular immune response pathway, has attracted much attention in tumor immunotherapy. However, low metabolic stability of conventional STING agonists limits their clinical application. Recent study shows that chemotherapeutic drugs cisplatin and camptothecin (CPT) can activate cGAS-STING pathway and induce immune response by DNA damage. Nevertheless, the ability of chemotherapeutic drugs to activate STING is so weak that new strategies are required to improve drug delivery efficiency for enhanced DNA damage, and then efficiently activate cGAS-STING pathway. Herein, we have developed a hybrid platinum prodrug (CPT-Pt (IV)) which can be triggered to release cisplatin and CPT in tumor cells. CPT-Pt (IV) with high hydrophobicity is further self-assembled with a ROS sensitive polymer (P1) and mPEG 2k -DSPE into ROS responsive nanoparticles (NPs). NPs could accumulate in the tumor site to release cisplatin and CPT, resulting in DNA double damage and finally activating cGAS-STING pathway, inducing DC cells maturation and increasing tumor infiltration of CD8 + T cells on colorectal cancer mouse model. This study showed that common DNA targeted drugs can activate the cGAS-STING pathway in situ via nano delivery system, and enhance the effect of chemotherapy and immunotherapy, which provide a new strategy for clinical antitumor therapy.
研究领域:
肿瘤学
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药学
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免疫学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Ke Zhang,Chengyao Huang,Yu Ren,Mingyue Zhang,Xiaotong Lu,Bangliu Yang,Peiran Chen,Shiyao Guo,Xueqian Wang,Yuhong Zhuo,Chao Qi,Kaiyong Cai
Tumor immunotherapy represents one of the most promising strategies for combating tumors by activating the immune system, harnessing anti-tumor immune cells to eliminate tumor cells, and preventing tumor recurrence and metastasis. However, clinical data indicate that the anti-tumor immune response is often inadequate in many cancer patients, resulting in the failure of tumor immunotherapy. Herein, we report a manganese (Mn)-based nanoadjuvant (denoted as BMP-Au) aimed at synergistically enhancing anti-tumor immune responses in breast cancer therapy through disulfidptosis-induced immunogenic cell death and Mn-mediated cGAS-STING pathway activation. BMP-Au is synthesized using bovine serum albumin as a biotemplate for biomimetic mineralization of manganese phosphate nanosheets, followed by the deposition of gold nanoparticles (Au NPs) on their surface. By exploiting the glucose oxidase-like activity of Au NPs alongside the Fenton-like reaction facilitated by Mn 2+ , BMP-Au orchestrates a cascade catalytic reaction that generates reactive oxygen species from glucose. This process not only initiates disulfidptosis but also leads to DNA fragmentation crucial for activating the cGAS-STING pathway. These concurrent mechanisms compromise cancer cell viability while significantly enhancing tumor immunogenicity, positioning BMP-Au as an innovative nanoadjuvant for cancer treatment that leverages both cellular stress mechanisms and immune activation.
研究领域:
肿瘤免疫学
·
纳米医学
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生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2025
·Vol. 10
·期 1
·1-17
·
IF 52.7
Tang Yu,Luo Zhiyuan,Ma Zhanni,Han Lingling,Zhou Yurong,Liang Tianci,Yang Kangsen,Zhao Lei,Chen Xiaoyuan,Zhang Pengfei
The variety and functionality of current clinical vaccine adjuvants remain limited. Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-mediated cellular immune responses, particularly tumor antigen-specific cytotoxic CD8 + T lymphocytes (CTLs), which are essential for effective cancer vaccine performance. Inspired by natural biomolecular condensates, we developed a versatile noncovalent protein self-assembly strategy distinct from traditional approaches requiring structural domain modifications or bifunctional crosslinkers. Our methodology employs amphiphilic molecules (sodium myristate/SMA and sodium dodecyl thiolate/SDT) as molecular bridges to mediate protein‒protein interactions through hydrophobic forces and disulfide bond formation. This process generates nanoscale protein condensate (PCD) vaccines with exceptional stability. As a novel adjuvant system, these synthetic condensates significantly enhance antigen cross-presentation by optimizing key parameters: antigen loading capacity, lymph node targeting, cytosolic delivery, and lysosomal escape. Consequently, they induce robust antigen-specific CTL responses and humoral immunity, demonstrating potent antitumor efficacy. Importantly, we found that the synthetic protein condensate (PCD) alone can act as a nanoadjuvant. By increasing mitochondrial membrane permeability, PCD induces mitochondrial DNA leakage into the cytosol, activating the cGAS‒STING pathway and promoting DC maturation. This safe and scalable platform eliminates the need for complex covalent modifications or genetic engineering, and it facilitates the design of diverse modular antigens, including neoantigens and viral antigens. Given its straightforward manufacturing process and superior immunogenicity, this synthetic PCD vaccine adjuvant has significant potential for clinical application and translation.
研究领域:
免疫学
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肿瘤学
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纳米医学
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分子生物学
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转化医学
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疫苗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xiaowen Hou,Chunlin Ren,Xiaodong Zeng,Yukun Hu,Yicheng Zhao,Yuxin Cheng,Qiusi Luo,Taotao Ding,Xue Qiao,Yuqin Liao,Guo-Bo Li,Bengui Ye,Xuechuan Hong,Yuling Xiao
DNA-targeting chemotherapies can activate the stimulator of interferon genes (STING) pathway but elicit limited immune responses. We engineered 3P-SN38 , a long-circulating nanoplatform enabling sustained, tumor-targeted SN38 delivery and NIR-II imaging. To further potentiate immune activation and minimize STING agonist toxicity, SR717 was co-encapsulated, forming 3P-SN38@SR717 . 3P-SN38@SR717 induced immunogenic cell death and dendritic cell maturation in vitro , with combination therapy showing superior effects. In vivo , 3P-SN38@SR717 effectively activated the cGAS-STING pathway, enhancing anti-tumor immunity. Significant increases in the populations of CD8 + T cells, mature dendritic cells, and M1-type macrophages were observed, along with elevated levels of cytokines, including IL-6 and TNF-α. This integrated nanoplatform offers a promising approach for chemoimmunotherapy, enabling durable tumor control with reduced dosing and improved safety.
研究领域:
纳米医学
·
免疫治疗
·
肿瘤学
·
药学
·
生物医学成像
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yuchen Zhang,Shuang Feng,Jie Luo,Kaige Xu,Junfeng Guo,Xingyue Zhang,Mengxue Yuan,Qiang Luo,Yu Huang,Chaoqiang Fan,Kibret Mequanint,Donghui Zhu,Malcolm Xing,Shiming Yang
The cGAS-STING signaling pathway effectively activates antitumor immune responses and holds promise for overcoming drug resistance in hepatocellular carcinoma (HCC) immunotherapy. However, achieving specific activation of this pathway in HCC remains challenging. Here, it is introduced a single-metal-doped nanoplatform, ZMRPF, which leverages ferroptosis-induced mitochondrial DNA (mtDNA) release to stimulate cGAS-STING-mediated immune activation. ZMRPF initiates HCC ferroptosis by inducing high levels of lipid reactive oxygen species, leading to mitochondrial stress and the release of endogenous mtDNA. This mtDNA synergistically activates the cGAS-STING pathway, enhanced by immunoactivating Mn 2 ⁺ ions released from ZMRPF. Concurrently, the tumor antigens released during ferroptosis amplify the activity of antigen-presenting cells, creating a cascade that links ferroptosis with innate immunity. This cascade drives a robust systemic antitumor immune response, effectively reversing the immunosuppressive microenvironment of HCC. These results demonstrate the ability of ZMRPF to reshape the immune microenvironment of HCC and offer a promising strategy for next-generation tumor immunotherapy.
研究领域:
肿瘤学
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免疫治疗
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纳米医学
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分子生物学
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癌症免疫学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）