Proof-of-Concept Evaluation of Primary Human FAP-CAR-NK Cells Targeting Activated Fibroblasts in Pulmonary Fibrosis

In recent years, the feasibility of immunotherapy targeting activated fibroblasts in pulmonary fibrosis has received further support. Recent studies have shown that transient FAP-targeted immunotherapy can alleviate pulmonary fibrosis by eliminating excessively activated fibroblasts, improving the aberrant extracellular matrix environment, and promoting alveolar cell lineage remodeling, suggesting that FAP-associated pathological stromal cells are amenable to therapeutic intervention. Based on this, research on FAP-centered engineered cell therapies is being gradually extended from settings such as myocardial fibrosis to pulmonary fibrosis. In this context, primary human NK cells represent a promising effector cell platform, as they are generally associated with a lower risk of severe treatment-related toxicities and relatively limited in vivo persistence, which may confer a more controllable therapeutic window. This feature is particularly important in fibrotic diseases, because long-term and continuous depletion of fibroblast populations may disrupt tissue homeostasis and injury repair. In addition, current studies of FAP-targeted CAR-NK therapy have mainly relied on NK cell lines such as NK-92, but these systems may not fully reflect the functional characteristics, receptor signaling, or clinical potential of primary human NK cells. Based on these considerations, it is necessary to develop a FAP-targeted cell therapy platform with greater clinical relevance for pulmonary fibrosis. In this study, we established a primary human FAP-CAR-NK-cell platform and conducted a proof-of-concept evaluation in pulmonary fibrosis-related models, including in vitro systems, a human pulmonary fibrosis-like Organoid model, and an acute in vivo observation model. The main novelty of this study lies in the use of primary human NK cells for FAP-targeted intervention in pulmonary fibrosis-related models. We focused on whether these engineered cells could selectively target and eliminate FAP-positive activated fibroblasts, retain effector function in a fibrotic microenvironment, and show short-term feasibility after adoptive transfer. The study was not intended to assess long-term therapeutic efficacy or systemic safety, but rather to examine the feasibility of FAP-directed fibroblast targeting by primary human CAR-NK cells in pulmonary fibrosis and to provide a basis for further preclinical investigation.