Chronic obstructive pulmonary disease reprograms the lung into an immune organ through trained immunity, cell death networks, and immune checkpoint dysregulation.

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous inflammatory disorder characterized by persistent immune dysregulation and progressive structural deterioration of the lung. However, how COPD reshapes lung architecture, immune signaling, and cellular identity at a systems level remains incompletely understood. Methods: We performed integrative, multi-dimensional transcriptomic analysis of human COPD lung datasets to evaluate alterations in immune signaling, regulated cell death pathways, fibrosis-associated programs, cell type-specific transcriptional identity, and immune checkpoint regulation. Genetic and cytokine-based perturbations targeting trained immunity pathways were analyzed to assess functional relevance. Results: COPD induced broad transcriptional activation of cytokines, secretory and plasma membrane proteins, CD markers, innate immune genes, and trained immunity genes. Deficiency of SET7, a promoter of trained immunity, or overexpression of IL-37, an inhibitor of trained immunity, attenuated expression of COPD-upregulated immune genes. COPD also promoted tissue injury through coordinated upregulation of genes regulating multiple forms of regulated cell death, including autosis, autophagy, parthanatos, immunogenic cell death, mitochondrial permeability transition-associated death, lysosomal cell death, apoptosis, necroptosis, ferroptosis, mitotic cell death, and proliferation-associated cell death. In parallel, COPD enhanced epithelial-to-mesenchymal transition and fibrosis-related transcriptional programs. Transcriptomic identity was disrupted in 10 of 14 major human lung cell types, with evidence of pathological trans-differentiation marked by aberrant expression of over 50 cell type-specific marker genes. Alveolar macrophages exhibited extensive dysregulation of immune checkpoint ligand; notably, PVR (CD155) expression was reduced in severe emphysema, while experimental PVR overexpression suppressed pro-inflammatory gene expression in both alveolar and interstitial macrophages. Additionally, COPD impaired the suppressive capacity of CD4 Discussion: Collectively, these findings demonstrate that COPD reprograms the lung toward an immune-like organ by promoting immune cell-like trans-differentiation of structural cells, activating diverse regulated cell death pathways, and altering immune checkpoint signaling. These mechanisms highlight potential therapeutic targets for immunomodulatory intervention in COPD.