Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel

Abstract

Tumours with an immunosuppressive microenvironment respond poorly to therapy. Activation of the stimulator of interferon genes (STING) pathway can enhance intratumoural immune activation, but STING agonists are associated with high toxicity and degrade prematurely, which limits their effectiveness. Here, we show that the extended intratumoural release of the STING agonist cyclic di-AMP transforms the tumour microenvironment from immunosuppressive to immunostimulatory, increasing the efficacy of antitumour therapies. The STING agonist was electrostatically complexed with nanotubes comprising a peptide–drug conjugate (a peptide that binds to the protein neuropilin-1, which is highly expressed in tumours, and the chemotherapeutic agent camptothecin) that self-assemble in situ into a supramolecular hydrogel. In multiple mouse models of murine tumours, a single low dose of the STING agonist led to tumour regression and increased animal survival, and to long-term immunological memory and systemic immune surveillance, which protected the mice against tumour recurrence and the formation of metastases. Locally delivered STING agonists could help to reduce tumour immunosuppression and enhance the efficacy of a wide range of cancer therapies.

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Fig. 1: Schematic and characterization of the in situ-formed chemoimmunotherapeutic supramolecular hydrogel.
Fig. 2: Biodegradable diCPT–iRGD nanotube hydrogel enables local retention and extended release of CDA.
Fig. 3: Local delivery of CDA by CPT-based NT hydrogels elicits regression of established GL-261 brain tumours.
Fig. 4: The important role of the STING pathway in stimulating innate and adaptive immune responses for effective tumour regression by CDA–NT.
Fig. 5: CDA–NT induces T-cell memory and a durable antitumour immune response.
Fig. 6: Local treatment with CDA–NT hydrogels promoted regression of low-immunogenic 4T1 breast cancers.

Data availability

All data supporting the findings of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

We thank M. Lim, J. Hanes and J. Fu from Johns Hopkins University School of Medicine for sharing the GL-261-luc, 4T1-luc and CT26 cells, respectively; and Q. Huang and Y. Guan for their support relating to cryosectioning. The research is supported by Johns Hopkins University Discovery Award. The flow cytometry study was partially supported by NIH grant nos. GM111682 and AI137719 (to F.Wan), and D.X. was supported by a Career in Immunology Fellowship from AAI.

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F.Wang and H.C. participated in the conception and design of the study. F.Wang and H.S. performed the majority of experiments and data analysis. F.Wang and D.X. performed the flow cytometry study and F.Wan helped to interpret the results. W.D., W.Z., Z.W., M.Z. and R.O. assisted with animal studies. F.Wang and H.S. analysed and interpreted the data. F.Wang, C.F.A. and H.C. designed and wrote the manuscript.

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Correspondence to Honggang Cui.

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Wang, F., Su, H., Xu, D. et al. Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel. Nat Biomed Eng (2020). https://doi.org/10.1038/s41551-020-0597-7

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