2. Academic Validation
  3. Autophagy suppression facilitates macrophage M2 polarization via increased instability of NF-κB pathway in hepatocellular carcinoma

Autophagy suppression facilitates macrophage M2 polarization via increased instability of NF-κB pathway in hepatocellular carcinoma

  • Int Immunopharmacol. 2023 Jul 24;123:110685. doi: 10.1016/j.intimp.2023.110685.
Zheng Gao 1,  Xiao-Gang Li 1,  Shan-Ru Feng 1,  Jia-Feng Chen 1,  Kang Song 1,  Ying-Hong Shi 1,  Zheng Tang 1,  Wei-Ren Liu 1,  Xin Zhang 1,  Ao Huang 1,  Xuan-Ming Luo 2,  Hai-Ying Zeng 3,  Qiang Gao 1,  Guo-Ming Shi 1,  Ai-Wu Ke 1,  Jian Zhou 4,  Jia Fan 5,  Xiu-Tao Fu 6,  Zhen-Bin Ding 7
Affiliations

Affiliations

  • 1 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
  • 2 Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China.
  • 3 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 4 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 5 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: fan.jia@zs-hospital.sh.cn.
  • 6 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China. Electronic address: fu.xiutao@zs-hospital.sh.cn.
  • 7 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China; Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China; Department of liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China. Electronic address: ding.zhenbin@zs-hospital.sh.cn.
PMID: 37494837 DOI: 10.1016/j.intimp.2023.110685
Abstract

The tumor microenvironment is a highly heterogeneous circumstance composed of multiple components, while tumor-associated macrophages (TAMs) are major innate immune cells with highly plastic and are always educated by tumor cells to structure an advantageous pro-tumor immune microenvironment. Despite emerging evidence focalizing the role of Autophagy in other immune cells, the regulatory mechanism of Autophagy in macrophage polarization remains poorly understood. Herein, we demonstrated that hepatocellular carcinoma (HCC) cells educated macrophages toward M2-like phenotype polarization under the condition of coculture. Moreover, we observed that inhibition of macrophage Autophagy promoted M2-like macrophage polarization, while the tendency was impeded when Autophagy was motivated. Mechanistically, macrophage Autophagy inhibition inactivates the NF-κB pathway by increasing the instability of TAB3 via ubiquitination degradation, which leads to the M2-like phenotype polarization of macrophages. Both immunohistochemistry staining using human HCC tissues and experiment in vivo verified Autophagy inhibition is correlated with M2 macrophage polarization. Altogether, we illustrated that macrophage Autophagy was involved in the process of HCC cells domesticating M2 macrophage polarization via the NF-κB pathway. These results provide a new target to interfere with the polarization of macrophages to M2-like phenotype during HCC progression.

Keywords

Autophagy; Hepatocellular carcinoma; Macrophage polarization; NF-κB pathway; TAB3.

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