Emerging insights into cell differentiation: the role of N-glycosylation in differentiation-based cancer therapies.

N-glycosylation is a dynamic post-translational modification that critically regulates cancer cell differentiation through modulating receptor signaling, cell adhesion, and plasticity. Aberrant N-glycosylation promotes dedifferentiation, drives EMT, and confers therapy resistance across malignancies. This review summarizes the role of N-glycosylation in determining lineage commitment and altering responses to differentiation therapies. Targeting the N-glycosylation apparatus can reprogram tumor cells toward differentiated phenotypes, potentiating the effects of agents such as ATRA and NaBu. Evidence from leukemia and solid tumors reveals the therapeutic potential of disrupting glycan-dependent cell fate decisions. Deciphering these "glycan codes" provides a framework for integrating glycosylation modifiers into precision differentiation therapies, offering novel strategies to overcome treatment resistance.