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

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 Pt^IV-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.

SUBMITTER: Zhang S

PROVIDER: S-EPMC10852989 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Zhang Shuren S Song Dongfan D Yu Wenhao W Li Ji J Wang Xiaoyu X Li Yachao Y Zhao Zihan Z Xue Qi Q Zhao Jing J Li Jie P JP Guo Zijian Z

National science review 20240117 1

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 t ...[more]

PMID: 38332843

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Project description:Certain types of cationic metal ions, such as Mn2+ are able to activate immune functions via the stimulator of interferon genes (STING) pathway, showing potential applications in eliciting antitumor immunity. How anionic ions interact with immune cells remains largely unknown. Herein, selecting from a range of cationic and anionic ions, we were excited to discover that MoO42− could act as a cGAS-STING agonist and further confirmed the capability of Mn2+ to activate the cGAS-STING pathway. Inspired by such findings, we synthesized manganese molybdate nanoparticles with polyethylene glycol modification (MMP NDs) for cancer metalloimmunotherapy. Meanwhile, MMP NDs could consume glutathione (GSH) over-expressed in tumors and induce ferroptosis owing to high-valence Mo and Mn to elicit tumor-specific immune responses, which was further amplified by MMP-triggered the cGAS-STING activation. In turn, activated CD8+ T cells to secrete high levels of interferon γ (IFN-γ) and reduced GPX4 expression in tumor cells to trigger ferroptosis-specific lipid peroxidation, which constituted a “cycle” of therapy. As a result, the metalloimmunotherapy with systemic administration of MMP NDs offered a remarkable tumor inhibition effect for a variety of tumor models. Our work for the first time discovered the ability of anionic metal ions to activate the immune system and rationally designed bimetallic oxide nanostructures as a multifunctional therapeutic nanoplatform for tumor immunotherapy. Graphical abstract Metal cations and anions with the strongest cGAS-STING activation were screened using 293-Dual™ mSTING cells and then employed to construct bimetallic oxide MMO NDs, which were then modified with DSPE-PEG to obtain MMP NDs. MMP NDs containing Mn2+ and MoO42− showed effective cGAS-STING activation. After either local or systemic administration, MMP NDs could consume the highly expressed GSH in tumor cells, break the redox balance, inhibit the activity of the GPX4 enzyme, and subsequently lead to ferroptosis of tumor cells. Tumor debris in the presence of MMP NDs would then trigger tumor-specific cell immunity.Image 1 Highlights • A variety of metal cations and anions were screened and discovered that Mn2+ and MoO42− had the most potent ability to activate the cGAS-STING pathway.• Bimetallic oxide manganese molybdate nanoparticles (MMP NPs) were constructed for amplifying cGAS-STING activation and inducing ferroptosis.• The activated CD8+ T cells secreted high levels of interferon γ (IFN-γ) and reduced GPX4 expression in tumor cells to constitute a “cycle” of therapy.• MMP NPs were able to reverse the immunosuppressive tumor microenvironment and simultaneously realize the dual functions of initiating and enhancing CIT.• Our work used ion screening as the basis for the construction of bimetallic oxides as a cancer immunotherapy nanomedicine platform.

Dataset Information

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

Publications

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

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