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

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

  • Signal Transduct Target Ther. 2023 Jan 20;8(1):22. doi: 10.1038/s41392-022-01212-7.
Keke Wei # 1,  Huafeng Zhang # 2,  Shuaishuai Yang 1,  Yuxiao Cui 3,  Bingxia Zhang 4,  Jincheng Liu 3,  Liang Tang 1,  Yaoyao Tan 3,  Simin Liu 1,  Shiqi Chen 4,  Wu Yuan 3,  Xiao Luo 2,  Chen Chen 3,  Fei Li 1,  Junwei Liu 4,  Jie Chen 5,  Pingwei Xu 6,  Jiadi Lv 5,  Ke Tang 3,  Yi Zhang 7,  Jingwei Ma 8,  Bo Huang 9 10
Affiliations

Affiliations

  • 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.
  • 8 Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China. majingwei@hust.edu.cn.
  • 9 Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China. tjhuangbo@hotmail.com.
  • 10 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. tjhuangbo@hotmail.com.
  • # Contributed equally.
PMID: 36658134 DOI: 10.1038/s41392-022-01212-7
Abstract

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-β release. 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 CA2+ 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-β production. 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.

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