Glycosylation converts CD24 from a developmental marker into a glyco-immune checkpoint in B-cell acute lymphoblastic leukemia.

CD24 is widely recognized as a developmental marker of early B-cell differentiation and is highly expressed in precursor B-cell acute lymphoblastic leukemia (B-ALL). However, CD24 expression alone does not fully explain its biological activity, suggesting that post-translational regulation, particularly glycosylation, may determine its immune-regulatory functions. Although the CD24-Siglec-10 axis has emerged as an important innate immune checkpoint, how developmental CD24 expression is functionally adapted during leukemogenesis remains poorly understood. Here, we propose a framework in which CD24 functions as a glyco-immune checkpoint whose activity is determined by functional glycoforms rather than protein abundance alone. We discuss how physiological CD24 expression during B-cell ontogeny may contribute to developmental immune tolerance and propose that this program can be retained, hijacked, or remodeled during leukemogenesis through altered glycosylation patterns. Such glyco-adaptation may enhance CD24-Siglec-10-mediated suppression of macrophage surveillance, allowing leukemia cells to evade innate immune recognition and persist as minimal residual disease. We further propose that glycosylation-dependent immune adaptation represents an additional layer of leukemia evolution that complements genetic and epigenetic alterations. This perspective integrates developmental biology, glycobiology, innate immunity, and leukemia biology to establish the emerging field of leukemia glycoimmunology. Finally, we discuss the translational implications of CD24 glycobiology, including glycoform-based biomarkers, functional immune profiling, glycosylation-directed therapeutic strategies, and modulation of glycan remodeling pathways. Understanding how glycosylation shapes CD24 function may provide new opportunities for precision immunotherapy in B-ALL.