ICAM-2 is a type I transmembrane glycoprotein containing two extracellular Ig superfamily domains, a hydrophobic transmembrane region, and a short cytoplasmic domain, constitutively expressed on various cell types including T and B lymphocytes, macrophages, NK cells, monocytes, dendritic cells, neutrophils, endothelial cells, platelets, and CD34+ hematopoietic progenitor cells. ?Primarily localized to apical surface near intercellular junctions, ICAM-2 mediates cell binding to integrins like LFA-1 (αLβ2, CD11a/Cd18) and MAC-1 (αMβ2, CD11b/CD18) with strong implications in angiogenesis, inflammation, and cell survival. Specifically, it plays an essential role in lymphocyte adhesion, recruitment, trafficking, recirculation, and extravasation. ?ICAM-2 associates with ERM (ezrin/radixin/moesin) proteins to activate PI3K/Akt pathway and subsequently inhibit apoptosis in leukocytes and fibroblasts, while promoting capillary tube formation and junction maturation in endothelial cells via triggering of small GTPase Rac1activation. ?ICAM-2 is the only member of all ICAMs that maps to chromosome 17q23-25, a segment known for genomic instability and high aberration in cancers. ?ICAM-2 is refractory to pro-inflammatory cytokines such as IL-1, TNF-α, and IFN-γ, the very proteins that strongly upregulate ICAM-1 expression on endothelial cells both in vitro and in vivo.