摘要
The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment(TME).In this study,we constructed a manganese-based nano drug delivery system(NDDS)loaded with hydroxychloroquine(HCQ)for synergistic autophagy inhibition and STING activation-based immunotherapy.Hyaluronic acid(HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis.Subsequently,it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn^(2+)and HCQ simultaneously.As a kind of STING agonist,Mn^(2+)can bind to cGAS in tumor cells,activating the cGAS-STING pathway and generating typeⅠ-interferons(IFN-Ⅰ),which helped alleviate the immunosuppressive TME.Meanwhile,HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation,further sensitizing the cGAS-STING signal.Benefiting from this synergistic mechanism,HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment.Moreover,HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis.This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.
基金
supported by the National Natural Science Foundation of China(Nos.82172719,82102918)
Joint Funds of Henan Province Foundation for Science and Technology(No.232301420011).
