Exercise as a Mechanobiological Signal: A Mechanometabolic Framework Linking Force Sensing to Immune Adaptation

Exercise is commonly classified by external dose or metabolic demand, yet each bout also imposes spatially patterned mechanical loads on muscle, vessels, extracellular matrix, stromal niches, and mobile immune cells. This review asks whether that mechanical dimension can be organised into a testable framework linking exercise to immune biology. We conducted a critical mechanistic narrative synthesis of exercise physiology, mechanotransduction, immunometabolism, immune mechanobiology, and exercise epigenetics, with structured searches updated through 31 August 2026 and targeted citation checks through 8 September 2026; the studies underpinning the principal causal claims were appraised in duplicate, and their study-level basis is reported in a supplementary evidence table. Throughout, we label whether a mechanism has been demonstrated during exercise in vivo or only in non-exercise mechanical systems. Exercise-specific mechanosensing is well supported in skeletal muscle and endothelium and supported in stromal compartments, including Piezo1-dependent muscle stromal sensing and mechanosensitive bone-marrow niches, both currently demonstrated in mice. Immune cells also possess force-sensitive machinery, but this has been established almost entirely outside exercise, and direct human evidence for durable immune-cell epigenetic change after exercise is limited, short in duration, and does not establish a mechanical mechanism. We therefore propose the Mechanometabolic Immune Interface Model of Exercise (MIIM-E), a multiroute, falsifiable model that separates endothelium-mediated from leukocyte-intrinsic haemodynamic exposure, tissue-niche mechanotransduction, and systemic biochemical signalling, and that distinguishes tests of necessity, sufficiency, mediation, and incremental explanatory value. Persistence of an immune phenotype and its attribution to a mechanical cause are treated as separate hypotheses to be tested, not as assumed consequences of exercise. Mechanical information may contribute to immune adaptation, but its causal role depends on cell type, route, exposure, and persistence.