Mechanically Regulated Secretion: How Physical Forces Instruct the Secretory Pathway and Remodel the Secretome

Cells do not secrete in a vacuum: they continuously interpret mechanical and chemical stimuli. This "cell sociology" drives collective behaviors and communication networks, allowing cells to process information from their surroundings. Over the past decade, growing evidence shows that all major secretory organelles are responsive to mechanical cues, overturning the view of secretion as a purely biochemical process. Cues like extracellular matrix (ECM) stiffness, cell shape, membrane tension, and tissue deformation dynamically tune trafficking at every step, remodeling endoplasmic reticulum (ER) exit sites, reshaping Golgi architecture, redirecting sorting at the trans-Golgi network (TGN), repositioning endolysosomes, and controlling exosome release. This mechanical control operates through complementary transcriptional and post-translational mechanisms, including GTPase activation, kinase cascades, cytoskeletal tension, and lipid remodeling, enabling rapid organelle reconfiguration. A mechano-secretory feedback loop exists: the physical microenvironment reorganizes the secretory pathway, and the resulting secretome changes reshape ECM composition and tissue mechanics. While supporting physiological homeostasis, this loop dysregulation drives fibrosis, cancer progression, and immune dysfunction. In this review, we integrate recent major findings to provide a coherent framework for understanding how mechanical forces reshape the secretory pathway and influence tissue function and disease.