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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.

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Fig. 1: Amplifying STING activation with CMPs for cancer metalloimmunotherapy.
Fig. 2: Mn2+ augments IFN-I activity of STING agonists.
Fig. 3: CMPs co-delivering Mn2+ and STING agonist amplify STING activation.
Fig. 4: Local intratumoural administration of CMPCDA eliminates established tumours.
Fig. 5: Systemic i.v. administration of CMPCDA eliminates established tumours.
Fig. 6: Robust therapeutic effect of CMPCDA in multiple tumour models.

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Data availability

The authors declare that data supporting the findings of this study are available within the article and its Supplementary Information files. All relevant data can be provided by the authors upon reasonable request.

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Acknowledgements

This work was supported in part by the NIH (R01AI127070, R01CA210273, U01CA210152, R01DK108901, R01DE026728 and R01DE030691), a University of Michigan Rogel Cancer Center Support Grant (P30CA46592) and the University of Michigan, Michigan Drug Discovery (MDD21102). J.J.M. is supported by an NSF CAREER Award (1553831). L.W. was supported in part by the NIH (U24CA232979 and R01CA255242). X. Sun is supported by a Rackham International Student Fellowship and a Rackham Predoctoral Fellowship. We acknowledge J. Hong at the University of Michigan for helping with the ITC analysis, A. Dial at the Michigan Element Analysis Laboratory for Mn biodistribution analysis, K. Chinnaswamy at the University of Michigan Center for Structural Biology for helping with the protein thermal shift assay, J. Whitfield at the University of Michigan Cancer Center Immunology Core for ELISA analysis, H. Carlson at the University of Michigan for molecular dynamic analysis and Q. Zheng at Fujian Medical University Union Hospital for histological analysis. We also thank the University of Michigan Flow Cytometry Core, the ULAM (Unit for Laboratory Animal Medicine) In Vivo Animal Core (IVAC), and the University of Michigan Microscope Imaging Core for technical assistance. We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for the provision of MHC-I tetramers.

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Contributions

X. Sun, Y.L.L. and J.J.M. designed the experiments. X. Sun performed the experiments. Y.Z., J.L., K.S.P., K.H., X.Z., Y.X., J.N., J.X., X. Shi and L.W. helped with specific experiments. J.L. contributed to the western blotting assays. L.W. and Y.L.L. produced the NOOC1 model and characterized its mutational landscape and response profiles to immunotherapies. Y.X. contributed to the ELISPOT assay. X. Sun, J.L., L.W., Y.L.L. and J.J.M. analysed and interpreted the data. X. Sun, Y.L.L. and J.J.M. wrote the paper.

Corresponding author

Correspondence to James J. Moon.

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Competing interests

A patent application (WO2020014644A1) for CMP-based metalloimmunotherapy has been filed, with J.J.M. and X. Sun as inventors. Y.L.L. has licensed the NOOC1 model to Kerafast Inc. (catalogue number: EMU061). The remaining authors declare no competing interests.

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Sun, X., Zhang, Y., Li, J. et al. Amplifying STING activation by cyclic dinucleotide–manganese particles for local and systemic cancer metalloimmunotherapy. Nat. Nanotechnol. 16, 1260–1270 (2021). https://doi.org/10.1038/s41565-021-00962-9

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