ESAM (endothelial cell adhesion molecule) is a homophilic cell-cell adhesion mediator expressed on endothelial cells and specific dendritic cell subsets. Mechanistically, ESAM mediates cell-cell aggregation through homophilic molecular interactions 1 and plays critical roles in bicellular tight junction assembly and blood-brain barrier maintenance 2. ESAM regulates actin filament polymerization and cytoskeleton organization, contributing to adherens junction formation and intracellular protein localization 3. In dendritic cell biology, ESAM marks a subset of type 2 conventional dendritic cells (ESAM+cDC2s) that originate from transitional DC precursors and possess pDC-related developmental features 3. ESAM interacts with the prothrombotic protein Erbin in platelets; disruption of this interaction enhances mitochondrial oxidative phosphorylation and lipid metabolite secretion, promoting B cell-mediated antitumor immunity 4. Notably, ESAM expression is particularly high in megakaryocytes from cancer patients with metastasis 4. ESAM dysfunction is clinically associated with neurodevelopmental disorders characterized by intracranial hemorrhage, seizures, and spasticity, underscoring its importance in blood-brain barrier integrity and neurological function. These findings identify ESAM as a key regulator of endothelial homeostasis, immune cell development, and cancer-related pathological processes.