CAR T cells targeting fibroblast activation protein-α for the treatment of pulmonary fibrosis

Pulmonary fibrosis, a progressive and irreversible manifestation of interstitial lung disease, leads to severe respiratory dysfunction. Although current therapies can slow disease progression, they cannot eliminate pathogenic fibroblasts, thereby limiting clinical efficacy. Chimeric antigen receptor (CAR) T-cell therapy has shown success in hematologic malignancies and autoimmune diseases and is being explored for non-malignant disorders. Here, we identified fibroblast activation protein (FAP) as highly and selectively expressed in myofibroblasts and fibroblasts within fibrotic lung tissues via single-cell RNA sequencing analysis, indicating its potential as a therapeutic target. Using a bleomycin-induced mouse model, we confirmed FAP upregulation in fibroblast populations. Furthermore, we generated murine CAR T cells targeting FAP for the treatment of pulmonary fibrosis. The results showed that FAP-targeted CAR T cells significantly reduced fibrotic burden and improved pulmonary function, including mid-tidal expiratory flow (EF50), minute ventilation (MV), and tidal volume (TV). These results demonstrate the feasibility and therapeutic potential of FAP-targeted CAR T cells in eliminating pathogenic fibroblasts and provide a promising strategy for pulmonary fibrosis treatment.