Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAP α) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAP α enhanced tumor cell migration, invasion, epithelial–mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAP α in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAP α -activated prodrug, inhibited CRCLNM by targeting FAP α -positive LNM-CRC cells. Our study highlights the role of FAP α in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM. FAP α exhibits selective expression in lymph node metastatic colorectal cancer cells, facilitating colorectal cancer lymph node metastasis, which can be effectively inhibited by FAP α -activated prodrug Z-GP-DAVLBH. [Display omitted] [ABSTRACT FROM AUTHOR]