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 + Foxp3 + regulatory T cells through downregulation of key immunosuppressive genes, including those associated with FoxP3 + , TIGIT + , and LPS-responsive Tregs. Shared immunosuppressive gene signatures were identified between PVR-overexpression-inducing CD4 + T cells and IL-10-mediated regulatory pathways in T cells and monocytes. 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.