Mannose Metabolism and Its Anticancer Applications

Mannose is a naturally occurring hexose that enters cells via shared transporters with glucose and is phosphorylated to mannose-6-phosphate. This metabolite serves as a nexus between glycosylation pathways and central carbon metabolism, being interconverted by phosphomannose isomerase to fructose-6-phosphate for entry into glycolysis or glycan biosynthesis. In many cancers, mannose metabolism is rewired to support uncontrolled proliferation and to maintain glycoprotein folding and signalling. Therapeutically, exogenous mannose can overload tumour cells with mannose-6-phosphate, inhibiting key glycolytic enzymes, depleting ATP and triggering stress responses. Such metabolic perturbation impairs DNA repair and sensitises malignant cells to chemotherapeutic and radiotherapeutic regimens. Beyond direct cytotoxicity, mannose influences immune cell function and the tumour microenvironment, offering a multifaceted approach to anticancer intervention. Its global significance stems from the potential to repurpose a benign sugar as a selective metabolic adjuvant, enhancing efficacy and overcoming resistance across diverse tumour types.

Research from Nature Portfolio

Recent studies have demonstrated that inhibition of phosphomannose isomerase in acute myeloid leukaemia models markedly increases sensitivity to standard agents by diverting cells towards ferroptotic death. Accumulation of mannose-6-phosphate in these cells activates the ATF6 branch of the unfolded protein response, promoting lipid peroxidation and selective eradication of therapy-resistant clones. In parallel, supraphysiological D-mannose administration was shown to reprogramme inflammatory macrophages by raising intracellular mannose-6-phosphate, suppressing succinate-driven HIF-1α activation and curtailing IL-1β production. This metabolic interference not only dampens inflammatory signalling in endotoxaemia models but also highlights mannose’s capacity to modulate immune landscapes relevant to cancer progression and host defence.

Mannose Metabolism and Its Anticancer Applications publication trend

The graph below shows the total number of articles in mannose metabolism and its anticancer applications across all publications each year (not limited to Nature Index journals).

Technical terms

Mannose-6-phosphate: A phosphorylated sugar that accumulates upon mannose uptake and disrupts central metabolic pathways.

Phosphomannose isomerase (MPI): Enzyme converting mannose-6-phosphate to fructose-6-phosphate, linking mannose metabolism to glycolysis and glycosylation.

Ferroptosis: Iron-dependent cell death driven by lipid peroxidation, distinct from apoptosis.

Unfolded Protein Response (UPR): A stress signalling network triggered by misfolded proteins in the endoplasmic reticulum, influencing cell survival and death.

Glycolysis: Cytosolic pathway converting glucose (or fructose-6-phosphate) to pyruvate, generating ATP and metabolic intermediates for biosynthesis.

References

1. Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death. Nature Communications (2023).
2. D-mannose suppresses macrophage IL-1β production. Nature Communications (2020).
3. Mannose enhances the radio-sensitivity of esophageal squamous cell carcinoma with low MPI expression by suppressing glycolysis. Discover Oncology (2022).
4. ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase. Journal of Experimental & Clinical Cancer Research (2021).
5. Mannose: A Sweet Option in the Treatment of Cancer and Inflammation. Frontiers in Pharmacology (2022).