首页|Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer

Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer

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Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes(STING)agonists are promising cancer therapeutic regimens because they can amplify STING activation and remodel the immunosuppressive tumor microenvironment.However,a single molecular entity comprising both agents has not yet been developed.Herein,we designed two PtⅣ-MSA-2 conjugates(Ⅰ and Ⅱ)containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immune-activating STING agonist MSA-2;these conjugates showed great potential as multispecific small-molecule drugs against pancreatic cancer.Mechanistic studies revealed that conjugate I upregulated the expression of transcripts associated with innate immunity and metabolism in cancer cells,significantly differing from cisplatin and MSA-2.An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer(NK)cells into tumors and promote the activation of T cells,NK cells and dendritic cells in tumor tissues.These findings indicated that conjugate I,which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule,is a promising and potent anticancer drug candidate,opening new avenues for small-molecule-based cancer metalloimmunotherapy.

platinum drugSTING agonistsingle-molecule multitargetmetalloimmunology

Shuren Zhang、Dongfan Song、Wenhao Yu、Ji Li、Xiaoyu Wang、Yachao Li、Zihan Zhao、Qi Xue、Jing Zhao、Jie P.Li、Zijian Guo

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State Key Laboratory of Coordination Chemistry,School of Chemistry and Chemical Engineering,Chemistry and Biomedicine Innovation Center(ChemBIC),Nanjing University,Nanjing 210023,China

Department of Urology,Affiliated Drum Tower Hospital,Medical School,Nanjing University,Nanjing 210023,China

Nanchuang(Jiangsu)Institute of Chemistry and Health,Nanjing 210023,China

National Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNatural Science Foundation of Jiangsu ProvinceFundamental Research Funds for the Central UniversitiesJiangsu Specially Appointed Professor Plan,the Program for Innovative Talents and Entrepreneurs in JiangsuPostdoctoral Research Funding Program of Jiangsu ProvinceExcellent Research Program of Nanjing University

2019YFA09006600222930502229305122293052219770489205311192153303217310049195320122107047BK202020040205/14380225003503ZYJH004

2024

10.1093/nsr/nwae020

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ISSN：
年,卷(期)：2024.11(1)
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