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 (FAPα) 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 FAPα expression in HSCs. FAPα ⁺ HSCs promoted IL-18 secretion via NF-κB/NLRP3/caspase-1 signaling pathway, which facilitated extracellular matrix (ECM) remodeling and macrophage recruitment. By targeting FAPα ⁺ HSCs, the FAPα-activated prodrug Z-GP-DAVLBH disrupted the PMN and suppressed tumor liver metastasis. Collectively, our study emphasizes the crucial role of FAPα ⁺ HSCs in the liver PMN and provides a promising therapeutic strategy for tumor metastasis.