Sugar Storm: O-GlcNAc signaling amid the clouds of cancer complexity

Abstract Cancer is a systemic disease driven not only by cell-intrinsic alterations, but also by system-wide factors that regulate its initiation and progression. Among the key regulators of these processes are nutrient-sensing pathways, which coordinate both cellular and systemic responses. One such pathway involves O-linked N-acetylglucosaminylation (O-GlcNAcylation), a nutrient-responsive and reversible post-translational modification that has emerged as a critical driver of cancer progression. Catalyzed by O-GlcNAc transferase (OGT), O-GlcNAcylation integrates signals from glucose, glutamine, and other nutrients to regulate the activity of cytoplasmic, nuclear, and mitochondrial proteins. Recent studies demonstrate that O-GlcNAcylation influences multiple dimensions of cancer progression, including metabolic adaptation, transcriptional plasticity, immune evasion, metastasis, cancer stem-like states, and therapy resistance. Beyond its cell-intrinsic effects, O-GlcNAcylation also interfaces with broader systemic processes. In this review, we position O-GlcNAcylation within the framework of the “clouds of cancer complexity,” highlighting its roles across the metabolic effects, inception and promotion, pleiotropic immune responses, and aging systems and tissues clouds. We propose that O-GlcNAcylation functions as a systems-level integrator that embeds metabolic, environmental, and temporal signals into tumor evolution, revealing new conceptual and therapeutic opportunities.