ZNT1 and Zn 2+ control TLR4 and PD-L1 endocytosis in macrophages to improve chemotherapy efficacy against liver tumor

Dan Yang; Taikun Tian; Xiaojing Li; Baokai Zhang; Linlin Qi; Fang Zhang; Mingshun Han; Shuang Wang; Jun Xiao; Yingying Gou; Raorao Zhang; Qiaojie Liu; Sheng Su; Jiahui Liu; Xiaowu Huang; Qiang Gao; Lijian Hui; Huiru Tang; Yuncong Chen; Hongyan Wang; Bin Wei

doi:10.1097/HEP.0000000000000629

ZNT1 and Zn 2+ control TLR4 and PD-L1 endocytosis in macrophages to improve chemotherapy efficacy against liver tumor

Hepatology. 2023 Oct 9. doi: 10.1097/HEP.0000000000000629. Online ahead of print.

Authors

Dan Yang^{1

2

3}, Taikun Tian², Xiaojing Li², Baokai Zhang², Linlin Qi^{1

2

3}, Fang Zhang^{1

4}, Mingshun Han⁵, Shuang Wang⁵, Jun Xiao⁵, Yingying Gou², Raorao Zhang^{1

3}, Qiaojie Liu^{1

3}, Sheng Su⁶, Jiahui Liu⁷, Xiaowu Huang⁶, Qiang Gao⁶, Lijian Hui^{3

5

8}, Huiru Tang⁷, Yuncong Chen⁹, Hongyan Wang^{3

5

8}, Bin Wei^{1

2

3

4}

Affiliations

¹ State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
² School of Life Sciences, Shanghai University, Shanghai, China.
³ University of Chinese Academy of Sciences, Beijing, China.
⁴ Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
⁵ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
⁶ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
⁷ State Key Laboratory of Genetic Engineering, Zhongshan Hospital and School of Life Sciences, Metabolomics and Systems Biology Laboratory, Human Phenome Institute, Fudan University, Shanghai, China.
⁸ School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
⁹ State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC ), School of Chemistry and Chemical Engineering, Nanjing University.

PMID: 37816045
DOI: 10.1097/HEP.0000000000000629

Abstract

Background and aims: HCC is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc (Zn) deficiency. This study aims to understand how Zn could affect macrophage function and its application for HCC therapy.

Approach and results: Zn 2+ and the Zn transporter 1 (ZNT1, solute carrier family 30 member 1) were markedly reduced in intrahepatic macrophages from patients with HCC and from mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in patients with HCC. Critically, ZNT1 regulated endosomal Zn 2+ levels for endocytosis of toll-like receptor 4 and programmed cell death ligand 1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, Zn supplementation could reduce inflammation and surface programmed cell death ligand 1 expression in macrophages with the increased CD8 + T cell cytotoxicity, which synergized the antitumor efficacy of Sorafenib/Lenvatinib.

Conclusions: Our study proposes a new concept that ZNT1 and Zn regulate endosome endocytosis to maintain surface receptors, and Zn supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing programmed cell death ligand 1 + myeloid cells.