Metabolic reprogramming has been a hot topic in recent years, including glycolysis and lactic acid modification in recent years. Nowadays, "mannose" has also come into everyone's sight, leading to a new research angle.
On January 13, 2025, the team of Guideng Li of the Chinese Academy of Medical Sciences & Peking Union Medical College published an article entitled "Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity" in Cancer Cell. This article focuses on "sugar metabolism" in metabolic reprogramming and focuses on the new angle of "mannose". The research team adopted a multi-omics integrated research approach, using single-cell sequencing, Proteomics, metabolomics and Epigenetics to combine basic and clinical methods, not only explaining the differentiation of mannose metabolism regulating T cells, but also exploring it as an immunotherapy target, proving its clinical application potential.
Fig. 1 Integrated analysis identify impaired mannose metabolism as a intrinsic feature of exhausted CD8+ T cells; D-mannose-expanded T cells exhibit durable anti-tumor function; Enhanced mannose metabolism triggers T cell stemness differentiation. (Qiu, et al., 2025)
The authors applied mannose to T cells in vitro. Through single-cell metabolic analysis, it was found that D-mannose treatment changed the metabolic and epigenetic landscape of T cells, promoted stem cell characteristics, and enhanced anti-tumor effects.
Further through metabolomics, it was found that D-mannose regulates 312 metabolites of T cells. Glucose Metabolic Flux Analysis found that D-mannose treatment reduced glucose glycolysis and improved TCA Cycle. Seahorse assay showed that D-mannose increased the mitochondrial function of T cells.
Through metabolomics detection, it was found that D-mannose treatment increased the level of GlcNAc-1P and affected the HBP pathway. Western blotting and Co-IP detection found that D-mannose increased the expression of OGT and promoted the interaction between OGT and β-catenin.
Flow cytometry, transcriptome sequencing and in vivo experiments showed that D-mannose can promote the in vitro expansion of T cells, maintain the proportion of stem cell-like T cells, improve the anti-tumor activity of T cells, and reduce T cell exhaustion.
Single-cell metabolic analysis found that mannose metabolism disorder is associated with T cell exhaustion. D-mannose can change T cell metabolism and epigenetics, enhance its stem cell properties, make β-catenin more stable through OGT, and enhance anti-tumor ability. CITE-seq analysis showed that the number of stem cell-like T cells in the treated T cells increased and the number of exhausted T cells decreased.
After T cells were treated with D-mannose, metabolomics found changes in 312 metabolites. Glucose Metabolism Analysis showed that D-mannose reduced glycolysis and increased TCA cycle. Seahorse assay showed that D-mannose treatment enhanced mitochondrial function and reduced glycolysis. CUT&Tag-seq showed that D-mannose treatment changed gene modification and enhanced stem cell characteristics.
After T cells were treated with D-mannose, metabolomics found changes in UDP-GlcNAc and other factors, affecting the HBP pathway. Experiments showed that D-mannose treatment increased the levels of O-GlcNAcylated proteins and β-catenin, enhanced the expression of OGT and the interaction with β-catenin, activated Wnt signaling. Flow cytometry showed that D-mannose-treated T cells had enhanced anti-tumor effects.
In cell preparation experiments simulating clinical T cell therapy, it was found that D-mannose can amplify human T cells in vitro for a long time. T cells treated with D-mannose maintained a high stem cell-like ratio and high TCF1 expression, with strong anti-tumor activity and high persistence in tumor models, fewer exhausted T cells, more stem cell-like T cells, and better production of cytokines such as TNF-a, IFN-g, and IL-2.
This study has clarified for the first time the potential role of mannose in T cell exhaustion and tumor immunotherapy, and has also clarified the important prospects of D-mannose in promoting T cell activity and tumor immunotherapy. Metabolic reprogramming and sugar metabolism are currently hot topics, and combined with immune microenvironment, there are still many gaps worth exploring.
Reference
