Mechanical Regulation of the Immune System: From Sensory Mechanisms to Disease Pathogenesis

Biochemical signals have long dominated immunology, but mechanical force is now recognized as a fundamental regulator of immune cell behavior. Immune cells sense core mechanical cues via specialized mechanosensors, and dysregulated tissue mechanics in inflammation, fibrosis and tumors disrupt normal immunity. However, previous studies lack comprehensive integration of mechanical regulation across distinct immune cell lineages.

This review systematically synthesizes advances in mechanical immunology, covering the biophysical properties of primary mechanical forces, core mechanosensor functions, mechanotransduction mechanisms across innate and adaptive immune cells, and the pathological roles and therapeutic potential of immune mechanotransduction.

Mechanical signals regulate all critical immune cell functions through an interconnected mechanosensor network. Piezo1 mediates key processes in macrophages, neutrophils, T cells and B cells; integrins and the cytoskeleton-nuclear envelope complex transduce forces to modulate gene expression. Pathological mechanical niches drive immune dysfunction, and multiple mechanotherapeutic strategies show promising preclinical efficacy.

This review establishes a comprehensive framework for immune mechanical regulation, positioning mechanical immunology as a transformative biomedical frontier. It also identifies key unresolved challenges that will guide future research and the development of precision mechanotherapies.