Glycosylation as a dynamic regulator of RLR and cGAS-STING innate immune signalling pathways

Innate immune sensing by RIG-I-like receptors (RLRs) and the cGAS-STING pathway is tightly regulated by glycosylation. This review summarizes how distinct glycosylation modalities shape antiviral signaling at multiple levels. N-glycosylation in the ER-Golgi is essential for STING folding, stability, and signaling competence, whereas aberrant glycan states disrupt DNA sensing. In contrast, cytosolic O-GlcNAcylation dynamically modulates RLR-cGAS pathways by regulating MAVS aggregation, suppressing IRF3 and NF-κB activation, and interfering with cGAS-DNA binding. We further discuss crosstalk between glycosylation, ubiquitination, and phosphorylation, metabolic regulation of UDP-GlcNAc flux, and pathogen- or tumor-driven glycosylation reprogramming, highlighting glycosylation enzymes as potential immunomodulatory targets.