TSPAN15 is a tetraspanin protein that functions primarily as a critical regulator of ADAM10 trafficking and enzymatic activity. As a member of the TspanC8 subfamily, TSPAN15 interacts with the transmembrane metalloprotease ADAM10 to facilitate its exit from the endoplasmic reticulum and trafficking to the cell surface 1. Structurally, TSPAN15 acts as a molecular measuring stick that positions ADAM10's active site approximately 20 Å from the plasma membrane, enabling membrane-proximal substrate cleavage and influencing substrate selectivity 1. TSPAN15 stabilizes ADAM10 at the cell surface while negatively regulating Notch signaling by modulating ADAM10-mediated proteolysis 2. In disease contexts, TSPAN15 shows elevated expression in multiple malignancies. In pancreatic ductal adenocarcinoma, TSPAN15 promotes chemoresistance by sustaining integrin-β1 stability and suppressing ferroptosis through the FAK/AKT/mTOR-GPX4 cascade 3. In intrahepatic cholangiocarcinoma, TSPAN15-ADAM10-Notch1 signaling enhances cancer stem cell properties and chemoresistance 4. In hepatocellular carcinoma, TSPAN15 promotes autophagy-mediated EMT and metastasis via BTRC-dependent PDCD4 degradation 5. Genetically, TSPAN15 variants associate with venous thromboembolism susceptibility and chr10 thromboembolic pulmonary hypertension 67. Additionally, TSPAN15 supports alphavirus replication in astrocytoma cells 8.