The glucose-6-phosphatase system in cancer: from endoplasmic reticulum glucose-6-phosphate flux to stemness, immune escape, and therapeutic vulnerability.

The endoplasmic reticulum glucose-6-phosphatase (G6Pase) system, traditionally linked to hepatic and renal glucose homeostasis, is increasingly recognized as a regulator of intracellular glucose-6-phosphate (G6P) partitioning with broad relevance to cancer biology. Emerging evidence implicates its catalytic subunits (G6PC1-3) and associated transporters, particularly SLC37A4/G6PT, in redox control, calcium homeostasis, protein quality control, glycogen metabolism, autophagy, epithelial-mesenchymal transition, stemness, immune evasion, and therapy resistance. In several non-gluconeogenic cancers, elevated G6Pase-system activity is associated with aggressive phenotypes, whereas in liver and kidney, G6PC loss promotes metabolic disruption and dedifferentiation. This Review highlights how ER-directed G6P flux, rather than glucose production itself, may shape tumour behaviour and reveal context-specific therapeutic vulnerabilities. Importantly, the clinical targeting of this system remains at an early, largely preclinical stage, and the therapeutic opportunities discussed here should be regarded as hypotheses to be tested rather than established interventions.