Mechanosensitive ion channels in immunity from biophysics to mechanomedicine.

Immune cells operate within a dynamic mechanical environment. Shear stress, matrix stiffness, membrane tension, and cellular traction continuously shape their fate and function. Mechanosensitive ion channels (MSICs) are the convergent molecular transducers of these forces. Five families dominate immune mechanotransduction: Piezo, TRPV4, K2P/TREK, TMEM63/OSCA, and ENaC. Each converts mechanical input into Ca²⁺, K⁺, or Na⁺ fluxes that drive the transcriptional and effector programs governing immune cell behavior. Two organizing principles that have emerged from the past decade of work structure this review. First, MSICs act as mechanical immune checkpoints. Their gating state controls T cell, NK cell, and dendritic cell function in stiff tumor stroma. This parallels the chemical checkpoints exploited by current immunotherapies. Second, MSICs display context-dependent functional polarity. The same channel produces opposite outputs depending on the magnitude, geometry, and timescale of the mechanical input. PIEZO1 has been reported to promote T cell activation under physiological shear in some experimental settings but restrain cytotoxicity in stiff stroma in others. It drives a pro-inflammatory macrophage phenotype in atherosclerosis but a tissue-reparative phenotype in sepsis. It restrains ILC2s acutely but drives type 2 pathology chronically. We integrate these principles with the structural biophysics of MSIC gating, contrasting force-from-lipid and force-from-filament mechanisms. We then trace MSIC function across macrophages, microglia, T cells, NK cells, dendritic cells, neutrophils, B cells, and innate lymphoid cells. We connect this biology to the emerging mechanomedicine toolkit: sonogenetics, magnetogenetics, force-responsive nanoparticles, organ-on-chip platforms, and engineered cellular therapies. Together, mechanical immune checkpoints and context-dependent polarity reframe immunity as a force-programmable system. This view positions MSICs as translational substrates for next-generation immunotherapies in cancer, autoimmunity, fibrosis, and chronic inflammation.