Combining cisplatin and a STING agonist into one molecule for metalloimmunotherapy of cancer.
Natl Sci Rev
; 11(1): nwae020, 2024 Jan.
Article
em En
| MEDLINE
| ID: mdl-38332843
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Natl Sci Rev
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
China