Open AccessTumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel
Author(s) -
Feihu Wang,
Hao Su,
Dongqing Xu,
Wenbing Dai,
Weijie Zhang,
Zongyuan Wang,
Caleb F. Anderson,
Mengzhen Zheng,
Richard Oh,
Fengyi Wan,
Honggang Cui
Publication year - 2020
Publication title -
nature biomedical engineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.961
H-Index - 56
ISSN - 2157-846X
DOI - 10.1038/s41551-020-0597-7
Subject(s) - sting , agonist , cancer research , stimulator of interferon genes , immune system , camptothecin , pharmacology , tumor microenvironment , medicine , immunotherapy , sensitization , toxicity , chemistry , immunology , receptor , innate immune system , biochemistry , engineering , aerospace engineering
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.