结直肠癌（CRC）是我国常见的恶性肿瘤之一，目前针对转移性CRC的治疗手段有限，患者预后较差。外泌体是肿瘤细胞与微环境之间的重要沟通桥梁。我们前期发现CRC细胞外泌体中的KLK6调节巨噬细胞M2型极化和炎症小体活化，促进CRC转移进程，但具体分子机制尚不清楚。根据预实验结果，我们初步提出“CRC细胞外泌体中KLK6蛋白被巨噬细胞摄取并入核，与PAX2蛋白结合并激活NLRP3转录，进而活化NLRP3炎症小体，调控肿瘤微环境中巨噬细胞极化，促进CRC转移”这一假说。本项目拟利用多种体内外模型，明确KLK6在CRC转移过程中的生物学功能；并结合生物信息学、相关分子生物学技术、高通量测序以及髓系基因敲除小鼠等深入探讨外泌体中KLK6调节巨噬细胞极化、促进CRC转移的具体分子机制。本项目的顺利开展有助于完善对KLK6在CRC转移中的功能及机制认识，并有望为转移性CRC的诊断和治疗提供新的分子靶点。

Colorectal cancer (CRC) is one of the most common malignancies in China. Metastatic CRC always indicates poor prognosis for limited effects and treatment options. Exosomes play an important role in communication between cancer cells and tumor microenvironment. In this study, we found that KLK6 in exosomes derived from CRC cells promoted NLRP3 inflammasome activation and M2 polarization in macrophages, thus resulting in CRC metastasis. However, mechanisms underlying the polarization of macrophages regulated by KLK6 and its involvement in CRC progression remained largely unknown. We hypothesized that KLK6 from CRC exosomes enhanced NLRP3 transcription and inflammasome activation via its interaction with PAX2 in the nucleus of macrophages, which promoted M2-like polarization of macrophages and ultimately CRC metastasis. This study is aimed to investigate the function of KLK6 in macrophage polarization and CRC metastasis both in vitro and in vivo. High-throughput sequencing, molecular biology assays, bioinformatic analysis and myeloid cell specific NLRP3-knockout mice models would be used to determine the underlying molecular mechanism. This study may not only contribute to a better understanding of the importance of KLK6 in CRC metastasis but also underscore KLK6 as a potential target for the diagnosis and treatment of CRC metastasis.