GlycoRNA in cancer immune regulation and progression: biological mechanisms and translational therapeutic prospects.

The emergence of glycosylated RNA (GlycoRNA) has expanded the paradigm of macromolecular glycosylation beyond proteins and lipids, revealing previously unrecognized layers of regulation within glycoscience and RNA biology. Increasing evidence suggests that GlycoRNA contributes to immune recognition and tumor progression. However, its biological functions and translational potential remain insufficiently characterized. GlycoRNAs are predominantly derived from small non-coding RNAs and are decorated with sialylated and fucosylated N- or O-linked glycans. Processed through canonical glycosylation pathways, they are displayed on the cell surface and contribute to tumor-immune interactions. Sialylated GlycoRNAs can bind sialic acid-binding immunoglobulin-like lectins on immune cells, generating inhibitory signaling that facilitates immune escape. Conversely, partial removal of glycans exposes modified uridine structures such as acp³U, which can activate Toll-like receptor-mediated innate immunity, indicating a glycan-dependent dual regulatory mechanism. Beyond immune regulation, alterations in GlycoRNA abundance are also associated with cancer cell migration, invasion, and metabolic adaptation. In metabolically stressful microenvironments, such as brain metastases, enhanced glycolysis increases substrates, including UDP-GlcNAc, which may further drive GlycoRNA modification and cell-surface presentation, establishing a positive feedback loop linking metabolic reprogramming to immune regulation. Given their stability on tumor cells and in circulation, GlycoRNAs represent promising biomarkers for liquid biopsy and emerging targets for immunotherapy. A comprehensive understanding of GlycoRNA glycosylation, structural determinants, and immune interactions will be essential to guide the development of diagnostic and therapeutic strategies in cancer.