CD99 is a transmembrane glycoprotein that serves multiple critical functions in immune cell biology and cellular homeostasis. Its primary function involves T-cell adhesion processes, leukocyte extravasation across endothelial barriers, and immunological synapse formation 1. CD99 facilitates leukocyte migration by helping cells overcome the endothelial basement membrane during extravasation, acting independently of PECAM1 1. Mechanistically, CD99 mediates actin-microtubule interactions through its transmembrane and cytoplasmic domains, with the cytoplasmic domain interacting with actin while the transmembrane domain binds microtubules 1. CD99 deficiency abolishes immunological synapse formation and prevents effective T cell immunity 1. Beyond immune function, CD99 regulates cellular differentiation and homeostasis, particularly in keratinocytes where it maintains tissue homeostasis and initiates early differentiation 2. In disease contexts, CD99 is highly expressed in Ewing sarcoma, serving as a diagnostic marker 3, and functions as an immune checkpoint target when PILRα on tumor cells interacts with CD99 on T cells to suppress antitumor immunity 4. Therapeutically, anti-CD99 antibodies show promise in cancer treatment by promoting tumor cell phagocytosis and reprogramming macrophages toward pro-inflammatory phenotypes 5, with potential for combination with immune checkpoint inhibitors 6.