Journal Article

Programmed initiation and enhancement of cGAS/STING pathway for tumour immunotherapy via tailor‐designed ZnFe2O4‐based nanosystem

Liang, Chun, Hou, Lin, Ji, Tianjiao, Zhang, Zhenzhong, Ma, Xu, He, Yuping, Chen, Youbai, Yang, Jing, Zhang, Qixu, Zhang, Meng, Liang, Chenglin, Li, Tongtong, Zu, Mali

2023

Overview

The cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signalling pathway has been a promising target for anticancer immunity, but rationally activating and enhancing this pathway in tumour cells is critical. Herein, a glutathione sensitive ZnFe2O4‐based nanosystem is developed to programmatically initiate and enhance the STING signalling pathway in tumour cells. The prepared ZnFe2O4 nanoparticles were coated with cancer cell membrane (CCM), which enabled the nanosystem target tumour cells. In tumour cells, ZnFe2O4 nanoparticles could be disintegrated by responding to high level glutathione, and the released Fe3+ generated reactive oxygen species to induce the DNA leakage into the cytoplasm to stimulate cGAS. Then Zn2+ promoted cGAS‐DNA phase separation to intensify the cGAS enzymatic activity. In addition, the low dose encapsulation of paclitaxel (PTX) acting as an antimitotic agent (ZnFe2O4‐PTX@CCM) ensured the sustained activation of cGAS/STING pathway. The in vitro and in vivo results confirmed that ZnFe2O4‐PTX@CCM elevated the cGAS/STING activity, promoted dendritic cell maturation, increased cytotoxic T lymphocyte and natural killer cells infiltration, eventually inhibiting the tumour progress and postoperative recurrence. This study provided feasible references on constructing STING activation nanosystem for tumour immunotherapy. Tailor‐designed ZnFe2O4‐based nanosystem can respond to the tumour microenvironment and stimulate anti‐tumour immune responses by enhancing the cGAS/STING pathway. Moreover, it remodels immunosuppressive microenvironment, and effectively inhibits tumour growth as well as postoperative recurrence.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adenosine monophosphate / AMP / Cancer / Cell activation / Cell division / Cell membranes / cGAS‐STING pathway / Cyclic GMP / Cytoplasm / Cytotoxicity / Dendritic cells / Deoxyribonucleic acid / Disintegration / DNA / DNA damage / Enzymatic activity / Glutathione / glutathione responsive / Immunotherapy / In vivo methods and tests / Lymphocytes / Lymphocytes T / Metastases / Nanoparticles / Natural killer cells / Paclitaxel / Particle size / Phase separation / Pore size / Reactive oxygen species / Reagents / Signal transduction / Spectrum analysis / Stimulators / Tumors / tumour immunotherapy / Zinc / Zinc ferrites / ZnFe2O4‐based nanosystem