肿瘤转移致癌死亡的90%以上，而目前尚无可用的治疗方法。然而，在此复杂过程中，基因的表观遗传调控仍存在有限的理解。本研究通过整合单细胞ATAC-seq（scATAC-seq）、单细胞RNA-seq（scRNA-seq）、微阵列、批量RNA-seq、免疫组化（IHC）染色以及来自配对原发性和肝转移性结直肠癌（CRC）患者来源的异种移植动物模型（PDX）和患者的蛋白组学数据集，发现肝转移性CRC细胞失去了其结肠特异的染色质可及位点，而获得了肝特异性的位点。重要的是，我们观察到肝转移性CRC细胞中肝脏特异性转录因子HNF4A的可及性增加。随后，我们对参与肝脏发育的细胞与肝转移性CRC细胞进行聚类分析，揭示了肝转移性CRC细胞的显著异质性。超过50%的肝转移性CRC细胞表现出与红细胞祖细胞和肝细胞相似的特征，表达与氧化磷酸化和糖酵解相关的基因增加。此外，我们的发现进一步揭示了这些细胞中MHC和IFN应答基因表现出适度的表观遗传活性，与免疫检查点阻断免疫疗法中低客观反应率显著相关。我们的研究结果揭示了HNF4A的关键作用，并且肝转移性CRC细胞中的细胞群可能作为关键的治疗靶点，用于处理肝转移和改善CRC患者的免疫治疗反应。版权所有 © 2023. Elsevier Ltd. 发表。

Tumor metastasis causes over 90% of cancer related death and no currently available therapies target it. However, there is limited understanding regarding the epigenetic regulation of genes during this complex process. Here by integrating single-cell ATAC-seq (scATAC-seq), single-cell RNA-seq (scRNA-seq), microarray, bulk RNA-seq, immunohistochemistry (IHC) staining, as well as proteomics datasets from paired primary and liver metastatic colorectal cancer (CRC) patient-derived xenograft (PDX) model and patients, we discovered that liver metastatic CRC cells lose their colon-specific chromatin accessible sites yet gain liver-specific ones. Importantly, we observed elevated accessibility of HNF4A, a liver-specific transcription factor, in liver metastatic CRC cells. Subsequently, we performed clustering analysis of liver metastatic CRC cells together with cells involved in liver development, revealing significant heterogeneity among the liver metastatic CRC cells. Over 50% of the liver metastatic CRC cells exhibited characteristics similar to those of erythroid progenitors and hepatocytes, showing increased expression of genes involved in oxidative phosphorylation and glycolysis. Moreover, our discovery further revealed that the MHC and IFN response genes in these cells exhibit moderate epigenetic activity, which is significantly associated with the low objective response rates in checkpoint blockade immunotherapy. Our findings uncovered the critical roles of HNF4A and the cell populations within liver metastatic CRC cells might serve as crucial therapeutic targets for addressing liver metastasis and improving the immunotherapy response in patients with CRC.Copyright © 2023. Published by Elsevier Ltd.