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 (FAPa) expression in LNM-CRC cells. Gain- or loss -function experiments demonstrated that FAPa enhanced tumor cell migration, invasion, epithelial -mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPa 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 FAPa-activated prodrug, inhibited CRCLNM by targeting FAPa-positive L NM -CRC cells. Our study highlights the role of FAPa in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NC - ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).