ICAM3 is a cell adhesion molecule that functions as a multivalent ligand mediating immune cell interactions and pathological processes. Primarily, ICAM3 serves as a ligand for integrin LFA-1 (ITGAL:ITGB2) on macrophages, facilitating recognition and phagocytosis of apoptotic neutrophils through an "engulfment synapse" mechanism 1. ICAM3 also acts as a CD209 ligand on dendritic cells, promoting DC-T cell clustering and T cell proliferation through calcium-dependent, integrin-independent signaling. Beyond homeostatic functions, ICAM3 has emerged as a pathological driver in cancer. ICAM3 expression correlates with TNM stage in breast and lung cancers, and functionally promotes metastasis via LFA-1 binding and ERM-mediated cytoskeletal reorganization 2. In cancer stem cells, ICAM3 recruits Src kinase through its intracellular YLPL motif, activating PI3K-AKT signaling to maintain stemness-associated transcription factors OCT4 and SOX2, while promoting chemoresistance 3. Multiple ICAM3 transcript variants enhance proliferation and epithelial-mesenchymal transition in diffuse large B-cell lymphoma 4. Clinically, elevated circulating ICAM3 associates with worse short-term functional outcomes in acute ischemic stroke 5, suggesting biomarker potential. Additionally, ICAM3 serves as a pathogen entry receptor for viral pathogens including KSHV and fungal allergens, linking it to infectious and allergic diseases.