Zhu Liye, Ning Qiting, Xue Jiang, Huang Shanpei, Chen Xingmei, Qiu Xinze, Chen Ni, Liang Shengmei, Huang Jiean, Liu Shiquan
Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, China.
Spinal and Orthopaedic Surgery Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
J Cancer. 2025 Jan 1;16(2):430-444. doi: 10.7150/jca.101011. eCollection 2025.
Relevant studies have demonstrated that plasma metabolites and immune cell characteristics are closely related to colorectal cancer (CRC). However, the causal relationship among these factors remains unclear, particularly regarding whether immune cell traits mediate the causal link between plasma metabolites and CRC. This study employed a two-step, two-sample Mendelian randomization (MR) using summary data from genome-wide association studies (GWAS) to assess causal associations between 1,400 plasma metabolites, 731 immune cell traits, and CRC. Additionally, it evaluated the mediating effect of immune cell traits and utilized single-cell RNA sequencing (scRNA-seq) to analyze immune cells infiltration in CRC, assess their metabolic functional changes and their interactions with CRC cells. Univariable two-sample MR analysis revealed causal relationships between 49 plasma metabolites and CRC, as well as between 36 immune cell traits and CRC. Two-step MR analysis revealed that two plasma metabolites (Sphingomyelin (d18:1/22:1, d18:2/22:0, d16:1/24:1) and 16α-hydroxy-DHEA-3-sulfate) influence CRC through two immune cell traits (SSC-A on CD14+ monocyte and CD3 on CD28- CD8+ T cell). Among these, SSC-A on CD14+ monocyte exhibited the highest mediating effect proportion, at 11.723%. scRNA-seq analysis further confirmed the increased infiltration of CD28- CD8+ T cells and CD14+ monocytes in CRC, along with upregulated sphingolipid metabolism and steroid biosynthesis. These cells were also found to interact with CRC cells, contributing to tumor initiation and progression. This study provides new evidence for the causal relationship between plasma metabolites and CRC, and it identifies immune factors with potential mediating roles. These findings offer new insights for further exploration of the mechanisms underlying the development of CRC.
相关研究表明，血浆代谢物和免疫细胞特征与结直肠癌（CRC）密切相关。然而，这些因素之间的因果关系仍不清楚，特别是免疫细胞特征是否介导了血浆代谢物与CRC之间的因果联系。本研究采用两步两样本孟德尔随机化（MR）方法，利用全基因组关联研究（GWAS）的汇总数据，评估1400种血浆代谢物、731种免疫细胞特征与CRC之间的因果关联。此外，研究还评估了免疫细胞特征的中介作用，并利用单细胞RNA测序（scRNA-seq）分析CRC中免疫细胞浸润情况，评估其代谢功能变化以及它们与CRC细胞的相互作用。单变量两样本MR分析揭示了49种血浆代谢物与CRC之间以及36种免疫细胞特征与CRC之间的因果关系。两步MR分析表明，两种血浆代谢物（鞘磷脂（d18:1/22:1、d18:2/22:0、d16:1/24:1）和16α-羟基脱氢表雄酮-3-硫酸盐）通过两种免疫细胞特征（CD14+单核细胞上的SSC-A和CD28-CD8+T细胞上的CD3）影响CRC。其中，CD14+单核细胞上的SSC-A表现出最高的中介作用比例，为11.723%。scRNA-seq分析进一步证实了CRC中CD28-CD8+T细胞和CD14+单核细胞浸润增加，同时鞘脂代谢和类固醇生物合成上调。还发现这些细胞与CRC细胞相互作用，促进肿瘤的发生和进展。本研究为血浆代谢物与CRC之间的因果关系提供了新证据，并确定了具有潜在中介作用的免疫因素。这些发现为进一步探索CRC发生发展机制提供了新见解。
