The immunodynamics of pulmonary fibrosis

Pulmonary fibrosis is the common end-stage pathological outcome of diverse interstitial lung diseases (ILDs), defined by progressive alveolar structural destruction, aberrant extracellular matrix (ECM) deposition, and ultimately fatal respiratory failure. For decades, idiopathic pulmonary fibrosis (IPF), the most lethal form of fibrotic ILD, was framed as a primarily epithelial-fibrotic disorder with minimal immune involvement, a paradigm supported by the failure of broad immunosuppressive therapies in clinical trials. However, advances in single-cell and spatial transcriptomics have redefined the role of the immune system in fibrosis, revealing that dynamic, context-dependent immune cell interactions-collectively termed immunodynamics-are central drivers of pathological lung remodeling across all fibrosing ILDs. In this review, we synthesize the spatiotemporal dynamics of innate and adaptive immune populations across disease stages, delineate the core molecular circuits that sustain immune-epithelial-mesenchymal crosstalk, and provide a critical evaluation of the successes and failures of immune-targeted therapeutic translation. We argue that the immunodynamics framework not only unifies the pathogenesis of IPF and secondary fibrotic ILDs, but also identifies actionable therapeutic windows and patient stratification strategies to advance precision treatment for these devastating diseases.