Fibroblast activation protein promotes natural killer cell invasion and tumor infiltration

Abstract Natural killer (NK) cells play essential roles in immunity, but their limited infiltration into solid tumors restricts their therapeutic potential. Here, we identify fibroblast activation protein (FAP), previously thought to be largely fibroblast-restricted, as a novel surface-expressed protease on human NK cells. Using genetic knockout, pharmacologic inhibition, and overexpression approaches, we demonstrate that FAP regulates NK cell migration, matrix invasion, and tumor infiltration in vitro and in vivo. FAP overexpression enhanced NK cell invasion through extracellular matrices, improved infiltration into tumor spheroids, and increased tumor cell lysis. In mouse xenograft models, FAP-overexpressing NK cells infiltrated tumors more effectively and significantly reduced tumor burden compared to wild-type NK cells. These findings reveal a previously unrecognized role of FAP in NK cell biology and suggest that engineering NK cells to enhance proteolytic migration may improve the efficacy of NK cell–based cancer immunotherapies.