Spatiotemporal Immune-Fibroblast Crosstalk in Pulmonary Fibrosis: From Failed Repair to Fibrotic Niche Formation

Abstract

Pulmonary fibrosis is a common and often fatal outcome of fibrosing interstitial lung diseases, characterized by progressive extracellular matrix deposition, destruction of alveolar architecture and irreversible loss of respiratory function. Although fibroblast activation and epithelial dysfunction are central to disease pathogenesis, fibrosis cannot be adequately explained by mesenchymal dysregulation alone. Rather, it represents a failure of multicellular repair regulation, in which immune cells, fibroblasts and epithelial populations reciprocally reshape cellular states, tissue niches and disease trajectories. Early innate immune responses amplify epithelial injury while simultaneously initiating provisional repair; however, when injury persists, these transient programmes fail to resolve and become stabilized into chronic profibrotic circuits involving monocyte-derived macrophages, dysfunctional T cells, inflammatory fibroblasts and matrix-producing myofibroblasts. Recent single-cell, spatial transcriptomic and lineage-tracing studies have revealed discrete cellular states, including SPP1⁺ scar-associated macrophages, inflammatory fibroblasts, CTHRC1⁺ myofibroblasts and tertiary-lymphoid-structure-associated stromal cells, that assemble multicellular, stage-specific and microanatomically restricted fibrotic niches. Collectively, these findings support a model in which soluble mediators, extracellular matrix mechanics, metabolic rewiring and immune-regulatory signalling cooperate to establish self-reinforcing stromal-immune circuits. In this Review, we synthesize current evidence for bidirectional immune-fibroblast crosstalk in pulmonary fibrosis, focusing on macrophage and T cell programmes, fibroblast-mediated immune regulation, spatiotemporal niche remodelling, mechanistic signalling networks, experimental models and therapeutic opportunities. We propose that progressive fibrosis reflects the spatiotemporal locking of pathological epithelial-immune-stromal circuits, a framework that may explain the limited efficacy of broad anti-inflammatory therapies in idiopathic pulmonary fibrosis and guide the development of more precise, stage-specific and combinatorial antifibrotic strategies.