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Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration

Nature Nanotechnology volume 17, pages 1322–1331 (2022)Cite this article

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Abstract

The clinical utility of stimulator of interferon genes (STING) agonists has been limited due to poor tumour-targeting and unwanted toxicity following systemic delivery. Here we describe a robust tumour-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolongs CDA circulation and efficiently targets tumours, mediating robust anti-tumour effects in a diverse set of preclinical cancer models at a single dose. Our findings reveal that ZnCDA enhances tumour accumulation by disrupting endothelial cells in the tumour vasculature. ZnCDA preferentially targets tumour-associated macrophages to modulate antigen processing and presentation and subsequent priming of an anti-tumour T-cell response. ZnCDA reinvigorates the anti-tumour activity of both radiotherapy and immune checkpoint inhibitors in immunologically ‘cold’ pancreatic and glioma tumour models, offering a promising combination strategy for the treatment of intractable human cancers.

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Fig. 1: Systemic administration of ZnCDA suppresses primary and metastatic tumour growth in mice.
Fig. 2: ZnCDA disrupts the tumour vasculature to enhance its deposition in tumours.
Fig. 3: IFN-γ instead of IFN-I is necessary for ZnCDA-induced tumour suppression.
Fig. 4: Tumour pre-existing T cells are sufficient and critical for the anti-tumour effect in T-cell-inflamed tumours.
Fig. 5: ZnCDA targets TAMs in the TME and modulates their antigen processing and presentation ability.
Fig. 6: ZnCDA combines with ICB or IR to overcome treatment resistance.

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary Information files. All raw sequencing data (SRA: PRJNA770747) are available online. The publicly available data used in this study are cited wherever relevant. Mouse reference genome (mm10): https://www.ncbi.nlm.nih.gov/grc/mouse; Molecular Signature Database: https://www.gsea-msigdb.org/gsea/msigdb/index.jsp.

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Acknowledgements

We are grateful to Z. Sun, A. Arina, S. P. Pitroda and T. Luo for helpful discussions, and R. Torres for technical assistance. We thank A. K. Huser for editing the manuscript. This work was supported by a grant from the Ludwig Foundation and an NIH grant (R01CA262508) to R.R.W., NIH grants (R01CA223184 and R01CA216436) to W.L. and NIH grants (R35CA232109 and R01AI141333) to J.P.Y.T. A.P. is the recipient of a Walter Benjamin scholarship provided by the German Research Foundation (Deutsche Forschungsgemeinschaft). J.B. was supported by a Clinical Therapeutics Training Grant (T32GM007019). We acknowledge the technical support from the University of Chicago Human Tissue Resource Center (RRID: SCR_019199), Animal Studies Core (P30CA014599), Microscopy Core (P30CA014599), Flow Cytometry Core (RRID: SCR_017760) and Mass Spectrometry Facility (CHE-1048528).

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Author notes

  1. These authors contributed equally: Kaiting Yang, Wenbo Han, Xiaomin Jiang.

Authors and Affiliations

  1. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA

    Kaiting Yang, Andras Piffko, Jason Bugno, Hua Liang, Wenxin Zheng, Liangliang Wang, Jiaai Wang, Xiaona Huang, Wenbin Lin & Ralph R. Weichselbaum

  2. The Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL, USA

    Kaiting Yang, Andras Piffko, Jason Bugno, Hua Liang, Wenxin Zheng, Liangliang Wang, Jiaai Wang, Xiaona Huang, Wenbin Lin & Ralph R. Weichselbaum

  3. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Wenbo Han, Xiaomin Jiang, Ziwan Xu & Wenbin Lin

  4. Taiji Group, Chongqing, China

    Wenbo Han

  5. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Andras Piffko

  6. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA

    Jason Bugno

  7. Peking University International Cancer Institute, Peking University Cancer Hospital and Institute, Peking University, Beijing, China

    Chuanhui Han

  8. Lineberger Comprehensive Cancer Center, Department of Genetics, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Sirui Li & Jenny P. Y. Ting

  9. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China

    Yang-Xin Fu

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Contributions

K.Y., W.H., W.L. and R.R.W. conceived the study; K.Y. designed the experiments; W.H. and X.J. prepared the nanoparticles; K.Y., W.H., X.J., A.P., C.H., S.L., Z.X., X.H., W.Z. and L.W. performed the experiments; K.Y. and J.W. performed mouse genotyping; K.Y., W.H., X.J. and A.P. analysed the data; J.B., H.L., J.P.Y.T. and Y.-X.F. contributed resources; K.Y., J.B., W.L. and R.R.W. drafted and finalized the manuscript with input from all other authors.

Corresponding authors

Correspondence to Wenbin Lin or Ralph R. Weichselbaum.

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Competing interests

R.R.W. has stock and other ownership interests with Boost Therapeutics, Immvira, Reflexion Pharmaceuticals, Coordination Pharmaceuticals, Magi Therapeutics and Oncosenescence. R.R.W. has served in a consulting or advisory role for Aettis, AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono, Nano proteagen, NKMax America and Shuttle Pharmaceuticals. R.R.W. has a patent pending entitled ’Methods and kits for diagnosis and triage of patients with colorectal liver metastases’ (US Patent application no. PCT/US2019/028071). R.R.W. has received research grant funding from Varian and Regeneron. R.R.W. has received compensation, including travel, accommodations or expense reimbursement, from AstraZeneca, Boehringer Ingelheim and Merck Serono. W.L. is the founder and chairman of Coordination Pharmaceuticals, which licensed the NCP technology from the University of Chicago. The other authors have no competing interests.

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Yang, K., Han, W., Jiang, X. et al. Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration. Nat. Nanotechnol. 17, 1322–1331 (2022). https://doi.org/10.1038/s41565-022-01225-x

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