| 5 | Chemo-drugs in cell microparticles reset antitumor activity of macrophages by activating lysosomal P450 and nuclear hnRNPA2B1显示文摘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. | 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 | 2023 | Signal Transduction and Targeted Therapy2023，8，2： | 0 |
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