The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

肝脏是一种免疫耐受器官，也是多种癌症类型的常见转移部位。尽管癌细胞侵袭程序的作用已得到很好的表征，但肝脏内在因素是否以及如何驱动转移性扩散尚不完全清楚。在这里，我们通过重新编程免疫抑制微环境表明，慢性肝病中异常激活的肝细胞内在细胞周期相关激酶 (CCRK) 信号传导对于癌症转移至关重要。使用诱导型肝脏特异性转基因模型，我们发现 CCRK 过表达显着增加了 B16F10 黑色素瘤和 MC38 结直肠癌 (CRC) 向肝脏的转移，后者被多形核髓源性抑制细胞 (PMN-MDSCs) 高度浸润并且缺乏自然杀伤 T (NKT) 细胞。PMN-MDSC 的消耗在黑色素瘤和 CRC 模型中， CCRK转基因小鼠恢复了 NKT 细胞水平及其干扰素 γ 的产生，并将肝转移降低至 2.7% 和 0.7%（转移性肿瘤重量）。从机制上讲，CCRK 激活核因子-kappa B (NF-κB) 信号传导以增加 PMN-MDSC 贩运趋化因子 CXC 基序配体 1 (CXCL1)，这与CCRK中的肝脏浸润性 PMN-MDSC 水平呈正相关转基因小鼠。因此，CRC肝转移患者表现出肝脏CCRK/NF-κB/CXCL1信号的过度激活，与健康肝移植供体相比，这与PMN-MDSCs的积累和NKT细胞的缺乏有关。总之，这项研究表明，肝脏 CCRK 信号传导的免疫抑制重编程破坏了抗转移免疫监视。我们的研究结果为肝转移干预提供了新的机制见解和治疗靶点。