As a professional mechanosensor, PIEZO1 converts mechanical stimuli—such as substrate stiffness, fluid shear stress, and membrane tension—into intracellular calcium influx, which in turn regulates a wide array of immune processes. The chapter details its significance across both innate and adaptive immunity, including T cell activation and migration, macrophage polarization, dendritic cell activation, natural killer cell cytotoxicity, neutrophil extracellular trap (NET) formation, and B cell antigen discrimination and class-switching to IgA. PIEZO1 emerges as a central regulator that fine-tunes immune responses by integrating signals from the cellular microenvironment, influencing inflammation, pathogen clearance, and metabolic reprogramming. Despite these advances, key questions remain regarding its role in chronic disease, autoimmunity, and cancer immunity. Targeting PIEZO1 presents a promising therapeutic strategy for conditions driven by mechanical stress and immune dysfunction, such as fibrosis, atherosclerosis, and solid tumours, potentially inaugurating a new era of mechano-immunotherapy.