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cyclic dinucleotide Self-Assembled Nanoparticles as a Carrier-Free Delivery Platform for STING-Mediated Cancer Immunotherapy

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CCS Chemistry 2024年第1期6卷 177-195页

作者： Lang Zhao Shao-Hua Zhuo Tian-Yang Wang Jun-Jun Wu Jing-Yun Su Wen-Hao Li Bo-Dou Zhang Yan-Mei Li Key Lab of Bioorganic Phosphorus Chemistry&Chemical Biology Department of ChemistryTsinghua UniversityBeijing 100084 Beijing Institute for Brain Disorders Beijing 100069 Center for Synthetic and Systems Biology Tsinghua UniversityBeijing 100084

cyclic dinucleotides(CDNs)are natural agonists of the stimulator of interferon genes(STING),which is an attractive immunotherapy ***,CDNs and their derivatives are being investigated ***,the poor bioavailability of exogenous CDNs has limited their application in *** nanocarriers are widely used for cytosolic delivery of CDNs,their loading capacity is insufficient,and their complicated composition and purification process raises bio-compatibility ***,we report a super-simplified CDN self-assembly strategy for carrier-free delivery of *** the presence of excess K^(+),CDNs form oligomers which further self-assemble with divalent metal ions(such as Mn^(2+))to form nanoparticles(NPs)in aqueous *** demonstrate that the self-assembled CDN NPs promote cellular uptake of CDNs and enhance tumor immunogenicity by remodeling the tumor microenvironment,inducing immunogenic tumor cell death and increasing tumorinfiltrating lymphocytes,which is conducive to the generation of tumor neoantigen-specific T-cell *** also demonstrate that the use of CDN NPs alone or in combination with immune checkpoint blockades inhibits tumor growth,highlighting the fact that CDN NPs are a potent platform for cancer immunotherapy.

关键词： cyclic dinucleotide STING carrierfree delivery tumor immunogenicity cancer immunotherapy

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Polymersome-mediated cytosolic delivery of cyclic dinucleotide STING agonist enhances tumor immunotherapy

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Bioactive Materials 2022年第10期7卷 1-11页

作者： Huan Zheng Beibei Guo Xinyun Qiu Yifeng Xia Yan Qu Liang Cheng Fenghua Meng Zhiyuan Zhong Biomedical Polymers Laboratory College of ChemistryChemical Engineering and Materials Scienceand State Key Laboratory of Radiation Medicine and ProtectionSoochow UniversitySuzhou215123PR China Department of Pharmaceutics College of Pharmaceutical SciencesSoochow UniversitySuzhou215123PR China

cyclic dinucleotides(CDNs)as stimulator of interferon genes(STING)agonists capable of inducing strong antitumor innate immune response are highly promising for tumor *** efficacy of these CDNs is,however,reduced greatly by their fast clearance,poor cell uptake and inefficient cytosolic ***,we report that reduction-responsive biodegradable chimaeric polymersomes(CPs)markedly enhance tumor retention and cytosolic delivery of a synthetic CDN,ADU-S100,and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes,giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN *** superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation,which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor *** development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.

关键词： Polymersomes STING agonists cyclic dinucleotide Immunotherapy Radiotherapy

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Emerging mechanisms and implications of c GAS-STING signaling in cancer immunotherapy strategies

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Cancer Biology & Medicine 2024年第1期21卷 45-64页

作者： Jiawen Zhang Sihui Yu Qiao Peng Ping Wang Lan Fang Tongji University Cancer Center Shanghai Tenth People’s HospitalSchool of MedicineTongji UniversityShanghai 200072China Reproductive Medicine Center Department of Obstetrics and GynecologyShanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 201620China Department of Obstetrics and Gynecology Zhongshan HospitalFudan UniversityShanghai 200032China

The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer *** this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key *** cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor ***,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer *** strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint *** approaches have shown promise in preclinical and clinical settings,by enhancing patient survival *** review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and ***,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy *** challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.

关键词： cGAS-STING pathway type I interferon cyclic dinucleotide STING agonist cancer immunotherapy

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