Ca&Mn dual-ion hybrid nanostimulator boosting anti-tumor immunity via ferroptosis and innate immunity awakening  

作　　者：Xi Deng Tianzhi Liu Yutong Zhu Jufeng Chen Ze Song Zhangpeng Shi Hangrong Chen 

机构地区：[1]State Key Laboratory of High Performance Ceramics and Superfine Microstructure,Shanghai Institute of Ceramics,Chinese Academy of Sciences,Shanghai,200050,PR China [2]Center of Materials Science and Optoelectronics Engineering,University of Chinese Academy of Sciences,Beijing,100049,PR China [3]School of Chemistry and Materials Science,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,310024,PR China [4]Nanotechnology and Intestinal Microecology Research Center,Shanghai Tenth People’s Hospital,School of Medicine,Tongji University,Shanghai,200072,PR China

出　　处：《Bioactive Materials》2024年第3期483-496,共14页生物活性材料（英文）

基　　金：supported by the National Key Research and Development Program of China(Grant No.2021YFB3801000);the National Natural Science Foundation of China(Grant No.32030061);the Basic Research Program of Shanghai Municipal Government(Grant No.21JC1406000);the Shanghai Sailing Program(Grant No.21YF1454200);Shanghai International Cooperation Project(Grant No.23490712900);All the animal experiments were performed with the approval of the Tongji University Experimental Animal Center,and the animal biomedical research authorization number is TJLAC-020-228.

摘　　要：Limited by low tumor immunogenicity and the immunosuppressive tumor microenvironment(TME),triple-negative breast cancer(TNBC)has been poorly responsive to immunotherapy so far.Herein,a Ca&Mn dual-ion hybrid nanostimulator(CMS)is constructed to enhance anti-tumor immunity through ferroptosis inducing and innate immunity awakening,which can serve as a ferroptosis inducer and immunoadjuvant for TNBC concurrently.On one hand,glutathione(GSH)depletion and reactive oxygen species(ROS)generation can be achieved due to the mixed valence state of Mn in CMS.On the other hand,as an exotic Ca2+supplier,CMS causes mitochondrial Ca2+overload,which further amplifies the oxidative stress.Significantly,tumor cells undergo ferroptosis because of the inactivation of glutathione peroxidase 4(GPX4)and accumulation of lipid peroxidation(LPO).More impressively,CMS can act as an immunoadjuvant to awaken innate immunity by alleviating intra-tumor hypoxia and Mn2+-induced activation of the STING signaling pathway,which promotes polarization of tumor-associated macrophages(TAMs)and activation of dendritic cells(DCs)for antigen presentation and subsequent infiltration of tumor-specific cytotoxic T lymphocytes(CTLs)into tumor tissues.Taken together,this work demonstrates a novel strategy of simultaneously inducing ferroptosis and awakening innate immunity,offering a new perspective for effective tumor immunotherapy of TNBC.

关 键 词：IMMUNOTHERAPY Ferroptosis Innate immunity STING signaling pathway Calcium carbonate nanoparticles MANGANESE 

分 类 号：R730.3[医药卫生—肿瘤]