Natural killer cell immunotherapy reverses lung fibrosis by eliminating senescent fibroblasts

Impaired immune clearance of senescent fibroblasts is a putative driver of pulmonary fibrosis. Exhausted natural killer (NK) cells have been implicated in this process, yet the underlying immune evasion mechanisms remain poorly understood. Using single-cell RNA sequencing (scRNA-seq) and spectral flow cytometry, we identified natural killer group 2 member A (NKG2A) as the predominant inhibitory checkpoint receptor expressed on NK cells in fibrotic lung diseases. Mechanistic in vitro coculture studies showed that NK cell suppression was mediated by senescent fibroblasts expressing human leukocyte antigen-E (HLA-E), the high-affinity ligand for NKG2A. scRNA-seq analysis of lungs from patients with idiopathic pulmonary fibrosis (IPF) further identified selective HLA-E expression in senescent HAS1+ fibroblast subsets. Further, spatial transcriptomics and multiplex immunofluorescence of patient lungs demonstrated that HLA-E+ fibroblasts were positioned at the periphery of fibroblast foci adjacent to NKG2A+ NK cells, establishing an immune-privileged niche. In contrast, extracellular matrix–producing myofibroblasts at the core of fibrotic foci lacked HLA-E and exhibited minimal NK engagement. In vivo, therapeutic blockade of NKG2A restored NK cell function, promoted clearance of senescent fibroblasts, and promoted fibrosis resolution in the bleomycin-induced mouse model. Monalizumab, a clinical-grade NKG2A inhibitor, reactivated patient-derived NK cells and enhanced lysis of human senescent fibroblasts in vitro. Together, these findings uncover a spatially restricted immune checkpoint axis that allows senescent fibroblasts to evade immune NK surveillance. Targeting the HLA-E/NKG2A axis represents a promising therapeutic strategy to restore NK cell–mediated immune clearance of senescent fibroblasts and reverse pulmonary fibrosis.