Developmental Sialylation in Neuroblastoma and Neural-Crest-Derived Tumors.

Pediatric malignancies are often closely linked to developmental cell states, differentiation trajectories, and restricted developmental windows. This relationship is especially evident in neural-crest-derived tumors, where malignant cells may retain, remodel, or reacquire glycosylation programs that normally regulate embryonic migration and lineage maturation. Using a pediatric developmental perspective, we consider tumor-associated sialylation as potentially reflecting retention of the developmental cell-of-origin glycome, reacquisition during malignant cell state plasticity, or cancer-specific remodeling. Neuroblastoma provides the strongest evidence linking these mechanisms to tumor biology and therapy. Polysialylated NCAM can support migratory and plastic phenotypes, ganglioside biosynthesis is coupled to adrenergic-mesenchymal cell state through cell state-dependent regulation of glycosyltransferases including ST8SIA1, and the developmentally enriched ganglioside GD2 creates an actionable therapeutic vulnerability. Selected neural-crest-derived tumors that also occur outside childhood are included as they may help distinguish lineage-associated mechanisms from features specific to pediatric malignancy. We examine sialoglycan-Siglec immune regulation, emerging glycan-directed therapies, and approaches for resolving sialylation across developmental and malignant cell states. This framework argues that pediatric neural-crest-derived tumors do not simply recapitulate embryonic glycosylation but selectively retain, remodel, or reacquire developmental sialylation programs that can influence plasticity, migration, immune evasion, and therapeutic response.