Pulmonary organoid models demonstrate compositionally driven epithelial plasticity and immune polarization

Aberrant epithelial regeneration and immune remodeling are hallmarks of chronic lung diseases such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. How cellular context shapes these trajectories remains unresolved. We present a lung organoid model that varies immune, epithelial, and mesenchymal inputs to reveal how composition dictates epithelial plasticity and macrophage polarization. We observed condition-dependent emergence of transitional cell states, including Sox9 ⁺ stressed progenitors, RAS-like intermediates, and hillock-like cells, alongside macrophage activation profiles. In mesenchyme-rich contexts, epithelial-immune-mesenchymal crosstalk reinforced inflammatory signaling and stabilized transitional cells, while immune-dominant inputs favored ATI-like repair and squamous remodeling. Hillock-like cells displayed context-dependent activation and expressed immune-regulatory genes, suggesting a role as epithelial orchestrators calibrating inflammatory response during regeneration. Regenerative outcomes were associated with multicellular signaling networks integrating stress sensing, immune coordination, and epithelial resilience. This platform facilitates modeling of milieu-specific regenerative mechanisms and informs strategies to redirect epithelial fate in chronic lung disease.