CD99 is an X/Y-linked transmembrane glycoprotein that escapes X-inactivation and plays central roles in leukocyte adhesion and extravasation. It facilitates T-cell adhesion and helps leukocytes cross the endothelial basement membrane during diapedesis, acting independently of PECAM1. CD99 exists in two isoforms with context-dependent functions in cell differentiation, migration, and protein trafficking. In normal hematopoiesis, CD99 constrains protein synthesis to maintain self-renewal capacity in hematopoietic stem cells. However, CD99 is upregulated in acute myeloid leukemia (AML) and leukemia stem cells, where it similarly suppresses protein synthesis to promote self-renewal and clonal expansion, implicating it in leukemogenesis 1. Histologically, Ewing sarcoma—the second most frequent bone tumor in children and adolescents—is characterized by high CD99 expression in its small round cells 2. In the tumor microenvironment, PILRα expressed on tumor cells suppresses antitumor T-cell immunity by targeting CD99 on T cells, inhibiting ZAP70/NFAT/IL-2/JAK/STAT signaling 3. Anti-PILRα antibodies blocking this interaction enhance T-cell antitumor function and show synergistic tumor suppression when combined with anti-PD-1 therapy 3. Anti-CD99 monoclonal antibodies themselves promote T-cell activation and tumor elimination, with potential for combination with immune checkpoint inhibitors.