Targeting pulmonary fibrosis with DDR2-specific chimeric antigen receptor macrophages

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a critical unmet need in therapeutic options. Chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein (FAP) have shown potential for IPF, but other cell-based approaches remain under-explored. In this study, we generated CAR macrophages (DDR2-CARM) targeting DDR2, a collagen receptor specifically upregulated in activated stromal cells, for the treatment of IPF. Murine DDR2-CARM exerted DDR2-specific phagocytosis, upregulation of antifibrotic cytokines, chemokines and matrix metalloproteinases in vitro; and mitigated pulmonary fibrosis in bleomycin-induced unilateral pulmonary fibrosis (UPF) mouse models by targeting DDR2 ⁺ stromal cells and degrading collagen. Single-cell RNA sequencing revealed that DDR2-CARM treatment led to attenuation of chronic inflammation accompanied by reduced infiltration of profibrotic neutrophils in the fibrotic lungs. Additionally, human DDR2-CARM suppressed fibrosis in precision-cut lung slices (PCLS) from IPF patients. Thus, DDR2 emerges as a new antifibrotic target, and DDR2-CARM represent potent remodelers of both stromal and immune activities in fibrotic tissues, holding therapeutic potential for IPF.