Macrophage-fibroblast communication driven by biomechanical stress in the pulmonary profibrotic niche: From signalling transduction to clinical translation.

Pulmonary (interstitial) fibrosis, the terminal pathological stage of various interstitial lung diseases, remains a major therapeutic challenge. The three approved antifibrotic agents - pirfenidone, nintedanib, and nerandomilast - receive only moderate endorsements in current guidelines, as they decelerate rather than arrest or reverse fibrotic remodelling, and none directly engages the mechanical dysregulation of the extracellular matrix (ECM) that underlies fibrogenesis. Macrophages and fibroblasts, two highly plastic cell populations, are the principal orchestrators of the pulmonary profibrotic niche: fibroblasts undergo profibrotic activation to become the dominant extracellular matrix (ECM) producers, while macrophages acquire profibrotic states that sense and amplify microenvironmental signals. Because the lung is an inherently mechanosensitive organ, biomechanical stress within the fibrotic niche emerges as a critical - yet therapeutically underexploited - dimension of their interaction. This review consolidates recent progress in understanding how biomechanical stress drives macrophage-fibroblast communication during pulmonary fibrogenesis. We first delineate the profibrotic activation of each cell type and their biomechanical interplay within the stiffening niche; we then examine the core mechanosensitive signalling mechanisms operating in fibroblasts and macrophages individually, their shared cell-state changes, and the direct and indirect crosstalk - encompassing membrane mechanosensors, integrin-FAK and Piezo1-YAP/TAZ pathways, secreted factors and extracellular vesicles - that closes a self-reinforcing mechano-chemical loop. Finally, we discuss the clinical translation of mechanosignalling-targeted antifibrotic therapies, from the limited mechanosensing engagement of approved drugs to current pipeline advances and the preclinical and clinical hurdles ahead. By framing fibrosis as a druggable biomechanical circuit, this review aims to inform strategies that halt - and potentially reverse - pulmonary fibrosis.