Chemo-drugs in cell microparticles reset antitumor activity of macrophages by activating lysosomal P450 and nuclear hnRNPA2B1  

作　　者：Keke Wei Huafeng Zhang Shuaishuai Yang Yuxiao Cui Bingxia Zhang Jincheng Liu Liang Tang Yaoyao Tan Simin Liu Shiqi Chen Wu Yuan Xiao Luo Chen Chen Fei Li Junwei Liu Jie Chen Pingwei Xu Jiadi Lv Ke Tang Yi Zhang Jingwei Ma Bo Huang 

机构地区：[1]Department of Immunology,Tongji Medical College,Huazhong University of Science&Technology,Wuhan 430030,China [2]Department of Pathology,School of Basic Medicine,Tongji Medical College,Huazhong University of Science&Technology,Wuhan 430030,China [3]Department of Biochemistry&Molecular Biology,Tongji Medical College,Huazhong University of Science&Technology,Wuhan 430030,China [4]Cardiovascular Surgery,Union Hospital,Huazhong University of Science&Technology,Wuhan 430071,China [5]Department of Immunology&National Key Laboratory of Medical Molecular Biology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences(CAMS)&Peking Union Medical College,Beijing 100005,China [6]Translational Medicine Laboratory,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325035,China [7]Biotherapy Center and Cancer Center,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第2期757-770,共14页信号转导与靶向治疗（英文）

基　　金：This work was supported by the Natural Science Foundation of China(81788101,32090053,91942314);CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-1-I2M-021);the Haihe Laboratory of Cell Ecosystem Innovation Fund(HH22KYZX0009);the Key R&D Program of Hubei Province(2020BCA068).

摘　　要：Macrophages in tumors(tumor-associated macrophages,TAMs),a major population within most tumors,play key homeostatic functions by stimulating angiogenesis,enhancing tumor cell growth,and suppressing antitumor immunity.Resetting TAMs by simple,efficacious and safe approach(s)is highly desirable to enhance antitumor immunity and attenuate tumor cell malignancy.Previously,we used tumor cell-derived microparticles to package chemotherapeutic drugs(drug-MPs),which resulted in a significant treatment outcome in human malignant pleural effusions via neutrophil recruitments,implicating that drug-MPs might reset TAMs,considering the inhibitory effects of M2 macrophages on neutrophil recruitment and activation.Here,we show that drug-MPs can function as an antitumor immunomodulator by resetting TAMs with M1 phenotype and IFN-βrelease.Mechanistically,drug molecules in tumor MPs activate macrophage lysosomal P450 monooxygenases,resulting in superoxide anion formation,which further amplifies lysosomal ROS production and pH value by activating lysosomal NOX2.Consequently,lysosomal Ca^(2+)signaling is activated,thus polarizing macrophages towards M1.Meanwhile,the drug molecules are delivered from lysosomes into the nucleus where they activate DNA sensor hnRNPA2B1 for IFN-βproduction.This lysosomal-nuclear machinery fully arouses the antitumor activity of macrophages by targeting both lysosomal pH and the nuclear innate immunity.These findings highlight that drug-MPs can act as a new immunotherapeutic approach by revitalizing antitumor activity of macrophages.This mechanistic elucidation can be translated to treat malignant ascites by drug-MPs combined with PD-1 blockade.

关 键 词：DRUGS LYSOSOMAL immunity 

分 类 号：R730.5[医药卫生—肿瘤]