Research Progress on Carbohydrate Metabolism in Immune Regulation, Cancer Therapy and Embryonic Development
Glucose is the transport form of carbohydrate in the blood and occupies a major position in the body's carbohydrate metabolism. The metabolic pathways of carbohydrate in the body mainly include Glycolysis, pentose phosphate pathway, uronic acid pathway, polyol pathway, glycogen synthesis and glycogenolysis, gluconeogenesis, and other hexose metabolism.
Here are a few recent studies summarized to understand the latest research ideas on carbohydrate metabolism.
The cell metabolic state profoundly affects the differentiation, persistence and anti-tumor efficacy of T cells.
On December 5, 2024, Li Guideng of Chinese Academy of Medical Sciences & Peking Union Medical College and Philip D. Greenberg's team at the University of Washington jointly published an article titled "Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity" in Cancer Cell. The study found that Mannose metabolism reshapes T cell differentiation and enhances anti-tumor immunity.
In this study, the research team found through single-cell metabolic analysis of T cells that reduced mannose metabolism is a prominent feature of T cell dysfunction. In adoptively transferred T cells, experimental enhancement/restoration of mannose metabolism by supplementing D-mannose can enhance anti-tumor activity and limit T cell exhaustion differentiation both in vitro and in vivo.
Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases O-GlcNAc Transferase (OGT)-mediated O-GlcNAcylation of β-catenin to maintain Tcf7 expression and epigenetic stemness, thereby promoting stem cell-like programs in T cells.
Furthermore, ex vivo expansion by supplementation with D-mannose yields adoptive T cells with stemness characteristics that show enhanced antitumor efficacy even after extensive long-term expansion.
Immunotherapy has demonstrated clinical efficacy and durable responses in different tumor types, therefore, identifying factors that control T cell persistence while limiting differentiation toward exhaustion is critical for designing rational strategies to prolong antitumor T cell responses. Cellular metabolism coordinates basic biological programs to maintain T cell homeostasis by utilizing intracellular fuels to generate energy and biosynthetic precursors necessary for T cell differentiation, proliferation, survival, and effector functions. Effector T cells rely on elevated glycolytic activity and one-carbon metabolism for rapid expansion and cytotoxicity, while stem-like T cells have enhanced fatty acid oxidation (FAO) and mitochondrial spare respiratory capacity (SRC) to facilitate long-term persistence.
Exhausted T cells display metabolic insufficiency, characterized by inhibition of both mitochondrial respiration and glycolysis. Unique environmental cues within the TME generate distinct metabolic regulatory mechanisms that influence T cell behavior. Previous studies have shown that an acidic TME can promote not only T cell dysfunction but also T cell stemness. Furthermore, metabolic stress and chronic antigenic stimulation in the TME impair mitochondrial fitness and reshape the epigenetic landscape, thereby hampering T cell antitumor immunity.
Fig. 1 Schematic diagram of the mechanism by which glucose metabolism reshapes T cell differentiation and enhances anti-tumor immunity. (Qiu, et al., 2025)
Here, the authors demonstrate that impaired mannose metabolism is a distinguishing feature of exhausted T cells, contributing to their dysfunction. Enhancing mannose metabolism in T cells by D-mannose treatment during ex vivo manufacturing promoted stem cell-like differentiation and sustained long-term expansion, leading to improved in vivo tumor control. D-mannose exposure induced intracellular metabolic programming and activated the Wnt signaling pathway via OGT, which mediated increased O-GlcNAcylation and β-Catenin stabilization, promoted Tcf7 expression and maintained epigenetic stemness. These findings highlight the role of mannose metabolism as a physiological regulator of T cell function and underscore its potential as a promising interventional target for immunotherapy.
Intermittent fasting can benefit cancer patients undergoing chemotherapy or immunotherapy. However, it is still uncertain how to select immunotherapy drugs to be combined with intermittent fasting. Here, the authors observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis and prolonged overall survival in mice with 4T1 and 4T07 breast cancer.
Fig. 2 Intermittent fasting limits progression of 4T1 and 4T07 tumor models. (Fu, et al., 2024)
During this process, both immunosuppressive monocytic (M-) and granulocyte (G-) myeloid-derived suppressor cells (MDSCs) decreased, while interleukin (IL) 7R+ and granzyme B+ T cells in the Tumor Microenvironment increased. The authors observed that Ly6Glow G-MDSCs decreased sharply after fasting treatment, and cell surface markers and protein mass spectrometry data showed potential therapeutic targets.
Mechanistic studies showed that glucose metabolic restriction inhibited the splenic granulocyte-monocyte progenitors and the production of colony-stimulating factor and IL-6, both of which contribute to the accumulation of G-MDSCs. On the other hand, glucose metabolic restriction can directly induce apoptosis of Ly6Glow G-MDSCs, but not of the Ly6Ghigh subpopulation. In summary, these results indicate that glucose metabolic restriction induced by fasting therapy weakens the immunosuppressive environment and enhances the activation of CD3+T cells, providing a potential solution for strengthening immune-based cancer interventions.
Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor in adults, characterized by high recurrence rate and high mortality rate. GBM patients with high ALDH1A3 expression have limited benefits from postoperative chemoradiotherapy, and exploring their resistance mechanism is crucial for the development of new therapies.
Studies have shown that the interaction between ALDH1A3 and PKM2 can enhance PKM2 tetramerization and promote lactate accumulation in GSCs. Scanning the lactylated proteome of lactate-accumulating GSCs revealed that XRCC1 was lactylated at K247, and lactylated XRCC1 had enhanced affinity with importin α, promoting its nuclear translocation and DNA repair. Through High-throughput Screening of small molecule libraries, it was found that D34-919 can effectively disrupt the ALDH1A3-PKM2 interaction and prevent the enhancement of PKM2 tetramerization. D34-919 treatment can enhance chemoradiotherapy-induced GBM cell apoptosis both in vitro and in vivo. In conclusion, ALDH1A3-mediated PKM2 tetramerization is a potential therapeutic target to improve the response of ALDH1A3hi GBM to chemoradiotherapy.
On October 16, 2024, the team of Berna Sozen from Yale University published an article titled "Selective utilization of glucose metabolism guides mammalian gastrulation" in Nature. The authors monitored two peaks of glucose uptake in the early mouse embryo, which gradually extended to the blastoderm and reappeared when mesenchymal cells migrated from the primitive streak to the wing of the mesoderm. Further studies revealed that this series of events was closely related to high ERK activity, indicating that the interaction between Glucose Metabolism and ERK signaling plays a key role in promoting the formation of embryonic tissue patterning. This study reveals how the selective utilization of glucose in different metabolic pathways guides embryonic morphological development.
Fig. 3 Two distinct waves of glucose metabolic activity selectively control cellular processes during mouse gastrulation.. (Cao, et al., 2024)
This study reveals the direct connection between metabolism and cell signaling during germ layer formation, and the dynamic fluctuations of glucose uptake during embryonic development affect cell behavior at specific developmental stages. The authors further revealed that glucose metabolism regulates ERK signaling through the HBP pathway, thereby affecting the fate determination of blastoderm cells. This study highlights the key role of selectivity in glucose metabolism in cell signaling regulation and provides a new perspective for understanding the complexity of cell behavior during development.
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