Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer
作者机构：State Key Laboratory of Coordination Chemistry School of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center (ChemBIC) Nanjing University Department of Urology Afflliated Drum Tower HospitalMedical SchoolNanjing University Nanchuang (Jiangsu)Institute of Chemistry and Health
出 版 物：《National Science Review》 (国家科学评论(英文版))
年 卷 期：2024年第11卷第1期
页 面：107-119页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：financially supported by the National Key R&D Program of China (2019YFA09006600) the National Natural Science Foundation of China (22293050, 22293051,22293052, 21977048, 92053111, 92153303, 21731004, 91953201and 22107047) the Natural Science Foundation of Jiangsu Province (BK20202004) Fundamental Research Funds for the Central Universities (0205/14380225) Jiangsu Specially Appointed Professor Plan the Program for Innovative Talents and Entrepreneurs in Jiangsu the Postdoctoral Research Funding Program of Jiangsu Province (003503) the Excellent Research Program of Nanjing University (ZYJH004)
主 题：platinum drug STING agonist single-molecule multitarget metalloimmunology
摘 要：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(Ⅰand Ⅱ) containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immuneactivating 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.
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