When RNA wears a sugar coat: Emerging biology and cancer relevance of GlycoRNA.

GlycoRNAs, a recently discovered category of covalently glycosylated RNA molecules that are predominantly enriched in small non-coding RNAs (sncRNAs) and reportedly displayed on the cell surface and within extracellular vesicles (EVs), have emerged as a novel signaling layer in cancer biology. Through specific interactions with sialic acid-binding immunoglobulin-like lectins (Siglecs), P-selectin, and heparan sulfate-vascular endothelial growth factor (VEGF) complexes, glycoRNAs may contribute to intercellular communication, inflammatory responses, and angiogenesis, highlighting their potential involvement in tumor progression and immune evasion. However, as glycoRNA research remains at an early stage, the clinical translation of glycoRNA-based findings is hindered by a series of fundamental unresolved questions. For instance, the biogenesis and trafficking mechanisms of glycoRNAs are still poorly defined, nucleotide-resolution maps of endogenous glycosylation sites are lacking, detection platforms have yet to be standardized and pervasive platform-dependent quantification bias has not been systematically addressed. In this review, we integrate current advances across the structural, mechanistic, and translational dimensions of cancer-associated glycoRNA biology, and propose a roadmap to advance the field from a fundamental biochemical curiosity toward a clinically actionable target in oncology.