TSPAN4 (tetraspanin 4) is a transmembrane protein that serves as a key regulator of migrasome formation, specialized cellular organelles that develop on retraction fibers of migrating cells 1. The protein functions by assembling tetraspanin- and cholesterol-enriched membrane microdomains into micron-scale macrodomains that swell into migrasomes, with tetraspanins and cholesterol being both necessary and sufficient for this process 1. Mechanistically, TSPAN4 acts as a membrane curvature sensor and contributes to migrasome structural stability through elevated membrane stiffness of enriched macrodomains 1. In disease contexts, TSPAN4 plays significant roles in cancer progression, where it promotes tumor cell migration, invasion, and metastasis across multiple cancer types including hepatocellular carcinoma, glioblastoma, and pancreatic cancer 234. TSPAN4-positive migrasomes facilitate intercellular communication by releasing signaling molecules and extracellular matrix proteins like PAK4 and LAMA4, and contribute to immunosuppressive tumor microenvironments 35. Additionally, TSPAN4 is implicated in age-related pathologies, where senescent border-associated macrophages produce migrasomes that induce paracrine senescence in microglia, contributing to cognitive aging 6.