ZNT1 and Zn2+ control TLR4 and PD-L1 endocytosis in macrophage to improve chemotherapy efficacy against liver tumor

Abstract

Background & Aims: Hepatocellular carcinoma (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 deficiency. This study aims to understand how zinc could affect macrophage function and its application for HCC therapy. Approach & Results: Zn2+ and the zinc transporter 1 (ZNT1, SLC30A1) were markedly reduced in intrahepatic macrophages from HCC patients and mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in HCC patients. Critically, ZNT1 regulated endosomal Zn2+ levels for endocytosis of TLR4 and PD-L1, 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, zinc supplementation could reduce inflammation and surface PD-L1 expression in macrophages with the increased CD8+ T cell cytotoxicity, which synergized the anti-tumor efficacy of Sorafenib/Lenvatinib Conclusions: Our study proposes a new concept that ZNT1 and zinc regulate endosome endocytosis to maintain surface receptors and zinc supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing PD-L1+ myeloid cells.