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.
Wu et al. (Tue,) studied this question.