Integration of mechanics and immunology: Perspective for understanding fibrotic disease mechanisms and innovating therapeutic strategies.

The treatment of fibrotic diseases has long posed a medical challenge due to the complex mechanisms underlying their occurrence and progression. Emerging evidence suggests that fibrosis development is influenced not only by biochemical factors but also by the activation of mechanotransduction in response to mechanical stimuli. Mechanoimmunology, an interdisciplinary field that examines how the immune system is influenced by physical forces and mechanical environments, has recently demonstrated significant importance and considerable potential for application in the study of fibrotic diseases. While the mechanisms by which biochemical signals regulate the immune system have been extensively explored, the progression of fibrosis is often impacted by both immune dysregulation and mechanical changes. During fibrosis, immune cells encounter strong mechanical stimuli, such as stiffer substrates and altered viscoelasticity, which activate their own mechanotransduction pathways and subsequently influence fibrosis progression. Targeting the mechanosensation of immune cells to enhance or inhibit their mechanoreception and mechanotransduction, thereby enhancing the anti-fibrotic role they play in the fibrotic process, could help innovate therapeutic strategies for fibrotic diseases. STATEMENT OF SIGNIFICANCE: Fibrotic disease progression is often associated with dysregulation of both tissue mechanical properties and immune responses. The fibrotic microenvironment's altered mechanical properties both result from and drive fibrosis, while immune cells actively sense and respond to these mechanical cues through mechanotransduction pathways. Emerging mechanoimmunology research highlights how mechanical stimuli influence immune cell behavior, yet the precise regulatory mechanisms remain unclear. This review examines mechanical communication in fibrosis, focusing on immune cells' mechanosensing capabilities and their role in disease progression, which helps to enhance our understanding of the pathogenesis of fibrosis and inform innovative strategies to open up mechano-immune pathways targeting fibrosis therapy.