Microenvironment mechanics, such as matrix stiffness, surface topography, cyclical stretch, etc., can be perceived by macrophages through receptors on the cell membrane, transmitted to the nucleus along the adhesion protein molecular chain and cytoskeleton, and also converted into biochemical signal to stimulate gene transcription. Furthermore, macrophages differentiate into specific phenotypes in response to various microenvironment mechanics and exhibit specific biological functions, such as adhesion, proliferation and migration, thus playing a significant role in disease progression and tissue regeneration. This study aims to elucidate the role and mechanism of microenvironment mechanics in macrophage polarization, and provides molecular biomechanics insights into the development of macrophage-targeting immunomodulatory biomaterials.