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Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy.

ABSTRACT: Nutritional metal ions play critical roles in many important immune processes. Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn²⁺. We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn²⁺ promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn²⁺ coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN-Mn²⁺ particle, CMP) that effectively delivered STING agonists to immune cells. The CMP, administered either by local intratumoural or systemic intravenous injection, initiated robust anti-tumour immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumour models. Overall, the CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy.

SUBMITTER: Sun X

PROVIDER: S-EPMC8595610 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy.

Sun Xiaoqi X Zhang Yu Y Li Jiaqian J Park Kyung Soo KS Han Kai K Zhou Xingwu X Xu Yao Y Nam Jutaek J Xu Jin J Shi Xiaoyue X Wei Lei L Lei Yu Leo YL Moon James J JJ

Nature nanotechnology 20210930 11

Nutritional metal ions play critical roles in many important immune processes. Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn<sup>2+</sup>. We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn<sup>2+</sup> promoted a 12- ...[more]

PMID: 34594005

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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

Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy.

Publications

Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy.

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