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
·
免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2025
·
IF 3
Jinlei Yun,Yindi Zhang,Hongyan Zhang,Fengkun Xiao,Yichun Wang,Peng Xu,Liping Qu
The members of Pleione (Orchidaceae) are popular worldwide for their ornamental appeal and medicinal properties. Pleione bulbocodioides , a CITES Appendix II-listed species, has been traditionally used in dermatological therapies but remains pharmacologically understudied. In this study, the in vitro anti-inflammatory effects of extracts from artificially cultivated P. bulbocodioides were investigated. We found the P. bulbocodioides extract (PE) significantly suppressed TNF-α/IFN-γ-induced expression of IL-6, IL-1β, CCL5, CCL8, CXCL8, CXCL3, and TMEM173 (STING) genes in both HaCaT cells and NHEKs. Transcriptomic analysis and Western blotting confirmed the inhibitory effects on STING/NF-κB signaling pathway of PE. And phytochemical characterization identified militarine and batatasin III as principal bioactive constituents responsible for STING/NF-κB pathway inhibition by PE. PE also demonstrated comparable anti-inflammatory efficacy in LPS-induced RAW 264.7 macrophages and SLS-irritated 3D reconstructed human epidermis. Thus, these findings indicate the potential of PE as a natural anti-inflammatory therapeutic or skincare ingredient for dermatological applications.
研究领域:
药理学
·
植物学
·
皮肤病学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2024
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IF 15.8
Yuhua Cao,Shuaishuai Ding,Yunping Hu,Lijuan Zeng,Jingrong Zhou,Ling Lin,Xiao Zhang,Qinghua Ma,Ruili Cai,Yu Zhang,Guangjie Duan,Xiu-wu Bian,Gan Tian
cGAS-STING signaling plays a critical role in radiotherapy (RT)-mediated immunomodulation. However, RT alone is insufficient to sustain STING activation in tumors under a safe X-ray dose. Here, we propose a radiosensitization cooperated with cGAS stimulation strategy by engineering a core–shell structured nanosized radiosensitizer-based cGAS-STING agonist, which is constituted with the hafnium oxide (HfO2) core and the manganese oxide (MnO2) shell. HfO2-mediated radiosensitization enhances immunogenic cell death to afford tumor associated antigens and adequate cytosolic dsDNA, while the GSH-degradable MnO2 sustainably releases Mn2+ in tumors to improve the recognition sensitization of cGAS. The synchronization of sustained Mn2+ supply with cumulative cytosolic dsDNA damage synergistically augments the cGAS-STING activation in irradiated tumors, thereby enhancing RT-triggered local and system effects when combined with an immune checkpoint inhibitor. Therefore, the synchronous radiosensitization with sustained STING activation is demonstrated as a potent immunostimulation strategy to optimize cancer radio-immuotherapy.
研究领域:
癌症生物学
·
纳米技术
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免疫学
·
放射肿瘤学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Pengyu Xue,Yinghan Wang,Xuefei Wang,Shilin Zhou,Xiaochen Wu,Lin Long,Chuanlong Guo
The incidence rate of breast cancer remains high, and lung metastasis often leads to treatment failure. Immunotherapy based on the cyclic guanosine monophosphate synthesis (cGAS) − interface gene stimulatory factor (STING) pathway is expected to bring benefits to the treatment of breast cancer. This study provided a delivery system based on fucoidan (Fu) and polyvinylpyrrolidone (PVP) for the potential molecule resveratrol (Res). The study confirmed that Fu and PVP were assembled into nanoparticles through hydrogen bonding and effectively loaded Res (Fu/PVP/Res). Interestingly, the adsorption of Zn 2+ (Fu/PVP/Res Zn 2+ ) was expected to provide impetus for the treatment of breast cancer. The results in vitro confirmed that Fu/PVP/Res Zn 2+ significantly inhibited the proliferation of breast cancer 4T1 cells, induced the accumulation of mitochondrial reactive oxygen species (ROS) and the damage of mitochondrial membrane potential (MMP), and further induced the cytoplasmic release of mtDNA, which was the direct cause of the activation of cGAS-STING pathway. In vivo studies confirmed that Fu/PVP/Res Zn 2+ treatment inhibited the growth of 4T1 transplanted tumors. Excitingly, Fu/PVP/Res Zn 2+ treatment also prevented lung metastasis of in situ tumors. The in vivo mechanism confirmed that Fu/PVP/Res Zn 2+ treatment activated the cGAS-STING pathway and induced abnormal expression of tumor apoptosis factors such as Bax/Bcl-2. In conclusion, our research provided potential for the treatment of breast cancer.
研究领域:
肿瘤学
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免疫学
·
药剂学
✓ 已验证
产品关联
DOI
高影响因子
Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-16
·
IF 11.3
He Qingbin,Zheng Runxiao,Ma Junchi,Zhao Luyang,Shi Yafang,Qiu Jianfeng
Background The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has attracted great attention for its ability to up-regulate innate immune response and thus enhance cancer immunotherapy. However, many STING agonists limit the further advancement of immunotherapy due to weak tumor responsiveness or low activation efficiency. The responsive and effective activation of cGAS-STING signaling in tumors is a highly challenging process. Methods In this study, a manganese-based nanoplatform (MPCZ NPs) was constructed that could responsively and efficiently generate more manganese ions (Mn 2+ ) and reactive oxygen species (ROS) to activate cGAS-STING signaling pathway. Briefly, manganese dioxide (MnO 2 ) was loaded with zinc protoporphyrin IX (ZPP) molecule and coated by polydopamine (PDA) embedded with NH 4 HCO 3 to obtain MPCZ NPs. Additionally, MPCZ NPs were evaluated in vitro and in vivo for their antitumor effects by methyl thiazolyl tetrazolium (MTT) assay and TUNEL assays, respectively. Results In this system, tumor responsiveness was achieved by exogenous (laser irradiation) and endogenous (high levels GSH) stimulation, which triggered the collapse or degradation of PDA and MnO 2 . Moreover, the release of Mn 2+ augmented the cGAS-STING signaling pathway and enhanced the conversion of hydrogen peroxide (H 2 O 2 ) to hydroxyl radical (·OH) under NIR laser irradiation. Furthermore, the release of ZPP and the elimination of GSH by MPCZ NPs inhibited HO-1 activity and prevented ROS consumption, respectively. Conclusions This adopted open source and reduce expenditure strategy to effectively generate more ROS and Mn 2+ to responsively activate cGAS-STING signaling pathway, providing a new strategy for improving immunotherapy.
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
Nano Today
·
2025
·
IF 10.9
Gang Feng,Yifan Wu,Xinzi He,Tingting Ye,Shang Chi,Xiaoxiao Ji,Jiawei Kang,Kaicheng Xu,JinFeng Zhou,Zhihui Xiang,Wei Wang,Yaping Li,Yiying Qi
Excessive friction and cellular senescence contribute to osteoarthritis (OA) development. However, synergistic treatments targeting these two causes of OA may have significant implications for OA. In this study, we propose a novel strategy for exosome delivery encapsulated an injectable and lubricated hydrogel to synchronously reduce the excessive friction and the accumulation of aged chondrocytes. A cartilage-targeting peptide HABP-PEG-COLBP was employed to achieve a stable and efficient lubrication. The zwitterions of phosphatidylcholine lipids secreted by the synovial membrane of the joint can adsorb water molecules, forming a hydrated layer around the charge. Moreover, the exosomes derived from bone marrow stem cell (BMSCs) were engineered with a chondrocyte affinity peptide (CAP) in the out membrane and si-STING in the exosome to reshape the senescence microenvironment. Furthemore, the in vivo data showed that the hydrogel/exosome delivery system successfully can alleviate the joint wear and rejuvenate chondrocytes to reverse the development of OA. The HD-T@CAP-Exos-siSTING gels can provide efficient lubrication and potentially alleviate friction-related diseases such as osteoarthritis. Teaser An injectable hydrogel delivering exosomes rejuvenates chondrocytes and reduces mechanical stress, presenting a potential osteoarthritis treatment strategy.
研究领域:
生物医学工程
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再生医学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
BIOMACROMOLECULES
·
2025
·
IF 5.4
Min Mu,Hui Li,Susu Xiao,Chenqian Feng,Bo Chen,Rangrang Fan,Nianyong Chen,Gang Guo
Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by rapid disease progression and a high risk of metastasis. The advent of immunotherapy has revolutionized the treatment paradigm for breast cancer. Herein, a manganese-based nanoagonist (FA-IR780/EGCG@MnO2) featuring mitochondrial targeting and photothermal therapy (PTT) was constructed for STING activation and photothermal metalloimmunotherapy. The engineered FA-IR780/EGCG@MnO2 was constructed to enable the generation of mitochondria-targeted reactive oxygen species under laser irradiation to release mitochondrial DNA (mtDNA) and induce immunogenic cell death. The released mtDNA, as an endogenous danger-associated molecular pattern, could activate the STING pathway. Concurrently, Mn2+ further enhanced the activation of the STING pathway. By combining the synergistically enhanced the activation of the STING pathway, the engineered nanoagonist facilitated the DC maturation and T lymphocyte infiltration, resulting in long-term immune memory to inhibit tumor growth. This study revealed the potential combination of metalloimmunotherapy and PTT for rational regulation of the immune microenvironment.
研究领域:
肿瘤学
·
免疫学
·
生物材料
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Shining Niu,Qian Chen,Lulu Yu,Xiao Wang,Haipeng Yu,Mei Wen,Zhigang Chen,Nuo Yu,Kun Li
Natural bacteria and bacterial bionics offer significant advantages in the synergistic approach to cancer treatments, while the development of such platforms remains challenging. Herein, bacterial membrane-coated chlorin e6-conjugated bacteriform manganese dioxide platform (BCBM) has been developed for amplifying phototherapeutic efficacy of tumors. The BCBM platform has been prepared by the in-situ growth of manganese dioxide on the surface of silica nanorods and subsequent etching process, photosensitizer conjugation, and bacterial membrane encapsulation. The manganese dioxide and bacterial membrane endow the BCBM with bacteria-like characteristics, enabling a specific response to the tumor microenvironment (TME). The manganese dioxide can react with hydrogen peroxide to produce large amounts of oxygen and manganese ions under acidic conditions. Upon near-infrared irradiation, the BCBM exhibits an excellent ability to generate reactive oxygen species because of sufficient oxygen supply. Furthermore, the released manganese ions activate cGAS-STING pathway, leading to the efficient apoptosis of cancer cells. The process of apoptosis is accompanied by the release of tumor-associated signaling molecules, which enhances therapeutic efficacy. Therefore, this work offers insights into designing biomimetic multifunctional nanoagents against cancers.
研究领域:
肿瘤学
·
生物材料
·
免疫治疗
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
IMMUNITY
·
2023
·
IF 32.4
Yanfei Hou,Zhimeng Wang,Peiyuan Liu,Xubiao Wei,Zhengyin Zhang,Shilong Fan,Lulu Zhang,Fangping Han,Yikang Song,Ling Chu,Conggang Zhang
Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but our understanding of how these signals are integrated into a cohesive immunometabolic program is lacking. Here, we have identified liver X receptor (LXR) agonists as potent inhibitors of STING signaling. We show that stimulation of lipid metabolism by LXR agonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover, we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectors for cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A), which is a 2′3′-cGAMP-degrading enzyme. Results of crystal structures suggest that cGAMP analog induces dimerization of SMPDL3A, and the dimerization is critical for cGAMP degradation. Additionally, we have provided evidence that SMPDL3A cleaves cGAMP to restrict STING signaling in cell culture and mouse models. Our results reveal SMPDL3A as a cGAMP-specific nuclease and demonstrate a mechanism for how LXR-associated lipid metabolism modulates STING-mediated innate immunity.
研究领域:
免疫学
·
代谢
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Hao Yu,Wenjing Liu,Kaikai Ding,Jiangjie Wu,Cheng Wang,Siyuan Wang,Lingyun Wu,Qiuying Tang,Xin Yin,Kan Jiang,Danfang Yan,Xu Wang,Si Chen,Senxiang Yan
Glioblastoma (GBM) remains a daunting oncological challenge because of its aggressive nature and resistance to conventional therapies. Inhibition of the intrinsic STING pathway in GBM hampers the effectiveness of immunotherapies. To overcome this clinical limitation, a Sequential Release HydroLipo System (SRHLS) is developed, in which hydrogels and nanoparticles are combined for controlled drug release. The SRHLS sequentially released decitabine and STING agonists, thereby correcting STING signaling dysfunction through epigenetic reprogramming and enhancing antitumor immunity. According to in vitro and in vivo experiments, the SRHLS reshaped the tumor microenvironment and markedly inhibited tumor growth, recurrence, and metastasis. These findings underscore the potential of the SRHLS as a promising therapeutic strategy for GBM.
研究领域:
肿瘤学
·
免疫疗法
·
药物技术
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Discovery
·
2025
·Vol. 11
·期 1
·1-14
·
IF 12.5
Wang Jinrui,Niu Shenghui,Hu Xiao,Li Tianxing,Liu Shengduo,Tu Yingfeng,Shang Zehua,Zhao Lin,Xu Pinglong,Lin Jingwen,Chen Lu,Billadeau Daniel D.,Jia Da
The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing to surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at the trans-Golgi network (TGN), which in turn phosphorylates IRF3 to induce type I interferon (IFN-I) expression. In contrast to STING, little is known about how TBK1 is transported to the TGN for activation. Here, we show that multiple TGN tethering factors, a group of proteins involved in vesicle capturing, are indispensable for STING-IFN-I signaling. Deletion of TBC1D23, a recently reported tethering factor, in mice impairs the STING-IFN-I signaling, but with insignificant effect on STING-NF-κB signaling. Mechanistically, TBC1D23 interacts with TBK1 via the WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, multiple TGN tethering factors were reduced in aged mice and senescent fibroblasts. In summary, our study uncovers that TGN tethering factors are key regulators of the STING-IFN-I signaling and suggests that their reduction in senescence may produce aberrant STING signaling.
研究领域:
免疫学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Huijiao Fu,Xiaoqiao Guo,Feng Fang,Cao Zhou,Yuanyuan Chen,Xuanbo Zhang,Bingchen Zhang,Xinran Li,Qiwen Liu,Jie Liu,Wei Chen,Ling Yu,Zhiqiang Yu,Xuefeng Wang
Cisplatin serves as the cornerstone medication in ovarian cancer (OC) chemotherapy; however, numerous resistance factors exist, resulting in unsatisfactory clinical treatment outcomes. Concurrently, OC frequently establishes an immunosuppressive microenvironment, which further exacerbates the challenges of cisplatin chemotherapy. Hence, it is particularly significant to explore a therapeutic approach capable of overcoming cisplatin resistance while reversing the immunosuppressive microenvironment of OC. Here, we synthesized a novel cisplatin polyprodrug (PTP) containing thioketal units, which self-assembled with a stimulator of interferon genes (STING) small-molecule agonist (SR-717) to form redox-smart-responsive PTP@SR-717 nanoparticles (NPs), enabling synergistic chemo-immunotherapy. Specifically, PTP@SR-717 NPs enhanced the anti-tumor effect of cisplatin through three key mechanisms: (i) Pre-target factors: Enhancing intracellular cisplatin uptake and reducing GSH-mediated detoxification to promote platinum accumulation. (ii) On-target factors: Utilizing molecular damage-associated molecular patterns (DAMPs) triggered by cisplatin to activate the STING pathway, thereby synergistically amplifying the STING-TBK1-IRF3 signaling and efficiently triggering an immune response. (iii) Post-target factors: Combining chemotherapy and immunotherapy to harness the immune system for tumor eradication. In conclusion, this study presents an effective approach to addressing the challenges associated with cisplatin in the clinical treatment of OC.
研究领域:
肿瘤学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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