血源性转移是结直肠癌肝转移（CRCLM）的主要途径。然而，作为肿瘤血管上的“守门人”，TPCs在血源性转移中的作用仍然大部分未知，这可能归因于对TPC分离缺乏特定生物标志物。在此，我们开发了一种联合显微切割和基于外包细胞培养基的方法，从CRCLM患者中获取TPCs。蛋白质组学分析显示，转导蛋白质通道相关因子2（TCAF2），即瞬时受体电位阳离子通道亚家族M成员8（TRPM8）的伴侣蛋白，在CRCLM患者的TPCs中过表达。TPCs中的TCAF2与肝转移、短期总生存率和无病生存率在CRC患者中呈正相关。增强和削弱功能实验证实了TPCs中的TCAF2促进肿瘤细胞运动性、上皮间质转化（EMT）和CRCLM，在外包细胞特定Tcaf2基因敲除小鼠中，这种效应减弱。在机制上，TCAF2抑制TRPM8的表达和活性，导致TPCs中Wnt5a的分泌，通过在肿瘤细胞中激活STAT3信号通路促进EMT。TRPM8激动剂薄荷醇显著抑制了TPCs和CRCLM中Wnt5a的分泌。本研究从冷感受受体的角度揭示了TPCs的前期转移效应，为CRCLM提供了有前景的诊断生物标志物和治疗靶点。© 2023年 作者。由Wiley-VCH GmbH出版的Advanced Science出版。

Hematogenous metastasis is the main approach for colorectal cancer liver metastasis (CRCLM). However, as the gatekeepers in the tumor vessels, the role of TPCs in hematogenous metastasis remains largely unknown, which may be attributed to the lack of specific biomarkers for TPC isolation. Here, microdissection combined with a pericyte medium-based approach is developed to obtain TPCs from CRC patients. Proteomic analysis reveals that TRP channel-associated factor 2 (TCAF2), a partner protein of the transient receptor potential cation channel subfamily M member 8 (TRPM8), is overexpressed in TPCs from patients with CRCLM. TCAF2 in TPCs is correlated with liver metastasis, short overall survival, and disease-free survival in CRC patients. Gain- and loss-of-function experiments validate that TCAF2 in TPCs promotes tumor cell motility, epithelial-mesenchymal transition (EMT), and CRCLM, which is attenuated in pericyte-conditional Tcaf2-knockout mice. Mechanistically, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion in TPCs, which facilitates EMT via the activation of the STAT3 signaling pathway in tumor cells. Menthol, a TRPM8 agonist, significantly suppresses Wnt5a secretion in TPCs and CRCLM. This study reveals the previously unidentified pro-metastatic effects of TPCs from the perspective of cold-sensory receptors, providing a promising diagnostic biomarker and therapeutic target for CRCLM.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.