Targeting FAPα-positive hepatic stellate cells ameliorates the formation of pre-metastatic niche

The pre-metastatic niche (PMN) serves as a catalyst for tumor metastasis and colonization, involving communication between immune cells and stromal cells. However, less is known about the specific cell-type and their organ-specific functions in PMN formation, with available therapeutic strategies still limited. Here, we identified a significant expression of fibroblast activation protein alpha (FAP α ) in hepatic stellate cells (HSCs) associated with the formation of liver PMN, which was dramatically attenuated in HSC-specific conditional Fap -knockout mice. Mechanistically, tumor cell-derived exosomal miR-2467-3p upregulated FAP α expression in HSCs. FAP α + HSCs promoted IL-18 secretion via NF- κ B/NLRP3/caspase-1 signaling pathway, which facilitated extracellular matrix (ECM) remodeling and macrophage recruitment. By targeting FAP α + HSCs, the FAP α -activated prodrug Z-GP-DAVLBH disrupted the PMN and suppressed tumor liver metastasis. Collectively, our study emphasizes the crucial role of FAP α + HSCs in the liver PMN and provides a promising therapeutic strategy for tumor metastasis.