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.

中文翻译：

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ZNT1和Zn2+控制巨噬细胞中TLR4和PD-L1的内吞作用以提高对肝肿瘤的化疗疗效。

背景 目的 肝细胞癌（HCC）与炎症和免疫调节密切相关，联合化疗与其他策略正在广泛研究以取得更好的疗效。肝癌伴有缺锌。本研究旨在了解锌如何影响巨噬细胞功能及其在 HCC 治疗中的应用。方法结果 HCC 患者和小鼠肝脏肿瘤的肝内巨噬细胞中 Zn2+ 和锌转运蛋白 1（ZNT1、SLC30A1）显着减少。较低的 ZNT1 表达与 HCC 患者较高的 IL-6 产生和较短的生存时间相关。至关重要的是，ZNT1 调节内吞 TLR4 和 PD-L1 的内体 Zn2+ 水平，从而减少巨噬细胞诱导的炎症和免疫抑制，从而预防肝脏肿瘤。小鼠中 ZNT1 的骨髓特异性缺失会增加慢性炎症、肝纤维化、肿瘤数量和大小。值得注意的是，补锌可以减少巨噬细胞中的炎症和表面PD-L1表达，同时增加CD8+T细胞的细胞毒性，从而协同索拉非尼/乐伐替尼的抗肿瘤功效。结论 我们的研究提出了一个新概念，即 ZNT1 和锌调节内吞作用以维持表面受体，锌补充剂可能与化疗协同治疗炎症相关肿瘤，特别是含有 PD-L1+ 骨髓细胞的肿瘤。