Vitronectin (VTN) is a multifunctional extracellular matrix protein with diverse roles in cell-matrix interactions, immune regulation, and tissue homeostasis. Primarily, VTN serves as a ligand for integrin-mediated signaling 1, facilitating cell adhesion and migration through integrin αvβ5 and other integrin receptors 2. Mechanistically, VTN regulates tissue remodeling via the urokinase plasminogen activator (uPA) signaling pathway 3 and modulates macrophage function through C1qbp interactions on tumor-associated macrophages 4. VTN has emerging disease relevance across multiple pathologies. In cancer biology, tumor-secreted VTN acts as an anti-phagocytic "don't eat me" signal that inhibits macrophage-mediated tumor clearance and shifts macrophages toward immunosuppressive M2-like subtypes 4. SPP1+ macrophages utilize VTN to promote liver cancer stemness through integrin αvβ5/AMPK/YAP1 signaling 1. In chr17 obstructive pulmonary disease, VTN dysregulation through altered uPA signaling contributes to emphysema development; Vtn-deficient mice exhibit exaggerated inflammation and emphysema 3. Additionally, VTN levels are dysregulated in non-alcoholic fatty liver disease and heart failure, where it associates with disease progression 56. Clinically, VTN represents a promising therapeutic target. Blocking the VTN-C1qbp axis combined with anti-CD47 immunotherapy enhances macrophage phagocytosis and reduces tumor growth in breast cancer models 4. Targeting integrin αvβ5/YAP1 signaling downstream of VTN sensitizes liver cancer to chemotherapy 1.