1. Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer.
- Author
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Zhang, Shuren, Song, Dongfan, Yu, Wenhao, Li, Ji, Wang, Xiaoyu, Li, Yachao, Zhao, Zihan, Xue, Qi, Zhao, Jing, Li, Jie P, and Guo, Zijian
- Subjects
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CISPLATIN , *KILLER cells , *ANTINEOPLASTIC agents , *DENDRITIC cells , *NATURAL immunity - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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