Youdaoplaceholder0 1.1 Hidden member of the sugar family ?

As the core energy substance of living organisms, the classification system of carbohydrates has long been solidified in textbooks: monosaccharides (such as glucose and fructose), oligosaccharides (such as lactose), and polysaccharides (such as starch). However, the particularity of mannose lies in its "dual identity" - it is not only a participant in energy metabolism but also a "password character" for cell communication. Mannose is widely present in a free state in the pectin layer of citrus fruits and the cell walls of deep-sea algae. In the human body, it becomes the molecular basis of key physiological processes such as immune recognition and cell adhesion through the N-link glycosylation modification of glycoproteins.

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Youdaoplaceholder0 1.2 Cognitive Iteration from Urinary Health to Cancer Pioneers ?

As early as the 1980s, the medical community discovered that mannose could prevent urinary tract infections by competitively inhibiting the adhesins of pathogenic bacteria. This mechanism has given rise to the hot sales of cranberry extract health products. But it was not until 2018 that a landmark study by Cancer Research UK (CRUK) in the journal Nature truly lifted the veil on its anti-cancer efforts: In a mouse model of pancreatic cancer, adding 20% mannose to drinking water reduced the tumor growth rate by 40%, and when combined with the chemotherapy drug gemcitabine, the survival period of the mice was extended by 2.3 times. This discovery has overturned the conventional perception that "all sugars promote cancer".

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Youdaoplaceholder0 Chapter 2 Decoding the Anti-Cancer Mechanism: Three "sugar locks" Unlock the Tumor's lifeline ?

Youdaoplaceholder0 2.1 Metabolic Hijacking: The "Trojan horse" disguised as glucose ?

The "Warburg Effect" of tumor cells enables their glucose uptake to be ten times that of normal cells. The CRUK team discovered through carbon-13 isotope tracing technology that mannose can infiltrate cancer cells through the same type of glucose transporter (GLUT1/3) with a structure similar to that of glucose. However, after entering, it is rapidly phosphorylated by hexokinase to mannose-6-phosphate (M6P). This metabolic intermediate cannot enter the glycolytic pathway but instead accumulates within the cell to form a "metabolic barrier", leading to the obstruction of ATP synthesis and the burst of reactive oxygen species (ROS), ultimately triggering apoptosis of cancer cells (Figure 1).

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Youdaoplaceholder0 2.2 Epigenetic regulation: Rewriting the "memory code" of cancer cells ?

In 2023, a research team from Fudan University in Cell Metabolism further revealed that mannose can act as an "epigenome editor". In the pancreatic ductal adenocarcinoma (PDAC) model, mannose treatment significantly reduced the acetylation level of the histone H3K27 site, resulting in the inhibition of the transcriptional activities of the oncogenes MYC and KRAS. Even more astonishingly, this apparent reprogramming effect is persistent - even when drug administration is stopped, cancer cells still maintain low invasiveness, providing new ideas for radical treatment.

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Youdaoplaceholder0 2.3 Immune microenvironment remodeling: Tearing off the "sugar-coated disguise" of PD-L1 ?

The same team found in subsequent studies that mannose can crack the immune escape mechanism of tumors by interfering with the glycosylation modification of programmed death ligand 1 (PD-L1). Mass spectrometry analysis revealed that mannose inhibited the N-glycosylation of asparagine at position 192 of the PD-L1 protein, resulting in its inability to fold correctly and anchor on the cell membrane. PD-L1, which loses the protection of the "sugar shield", is labeled by the E3 ubiquitin ligase FBXW41 and degraded by the proteasome. In melanoma mice, the combination of mannose and anti-PD-1 antibodies increased the complete tumor regression rate from 28% to 79% (Figure 2).

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Youdaoplaceholder0 Chapter 3 From Animal Models to Human Clinical trials: The Thorny Road of Translational Medicine ?

Youdaoplaceholder0 3.1 Breakthroughs and Limitations of Preclinical research ?

In the pancreatic cancer model of CRUK, although monotherapy with mannose delayed tumor progression, it failed to achieve complete remission. However, when combined with the FOLFIRINOX chemotherapy regimen, the median survival time of mice was prolonged from 42 days to 98 days, and there was no increase in toxicity. This result was reproduced in the triple-negative breast cancer model at MD Anderson Cancer Center: Mannose increased the tumor suppression rate of paclitaxel from 45% to 72%. However, researchers also found that approximately 15% of the tumors did not respond to mannose. Further analysis revealed that these drug-resistant cells highly expressed mannose-phosphate isomerase (PMI), which could convert M6P into fructose-6-phosphate and reconnect to the glycolytic pathway.

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Youdaoplaceholder0 3.2 A cautious dawn of human trials ?

The first Phase I clinical trial of mannose initiated in 2022 (NCT05220739) included 32 patients with advanced solid tumors. In the dose group of daily oral administration of 5g mannose, the circulating tumor DNA (ctDNA) levels of 8 patients decreased by more than 50%, among which the volume of liver metastases in one pancreatic cancer patient decreased by 31%. However, when the dose climbed to 10g, grade III diarrhea occurred in 3 patients, suggesting that the administration strategy needs to be optimized. At present, intravenous mannose preparations using nano-liposome encapsulation technology are under development. Preclinical data show that their tumor-targeted delivery efficiency reaches 78%, and their toxicity is significantly reduced.

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Youdaoplaceholder0 Chapter 4 Industrial Transformation and Controversy: The Real Challenges of the Sweet Revolution ?

Youdaoplaceholder0 4.1 Synthetic biology Solves the Mass production Puzzle ?

Naturally extracted mannose is costly (about per kilogram)

1200

It is difficult to meet the anti-cancer dose requirements (daily)

The approach is to increase the output to

The cost has dropped to1200), which is difficult to meet the anti-cancer dose requirement (10-20g per day). Synthetic biology giant GinkgoBioworks has increased the yield to 30g/L and reduced the cost to 50/kg by modifying the mannose-1 - guanosine phosphate transferase (MPG) pathway of Escherichia coli. More advanced technologies such as the CRISPR-Cas9-edited Saccharomyces cerevisiae engineered bacteria have been able to stably produce high-purity mannose during continuous fermentation.

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Youdaoplaceholder0 4.2 The Game between business Hype and scientific ethics ?

With the concept of "anti-cancer sugar" becoming popular, hundreds of mannose health products claiming to be "auxiliary treatment for tumors" have emerged on the Amazon platform, with price premiums as high as ten times. In 2023, the US FDA issued warning letters to 23 enterprises, emphasizing that "dietary supplements must not claim to have therapeutic effects on diseases." Scientists are concerned that blindly taking high doses of mannose may disrupt the intestinal flora - animal experiments have shown that long-term intake leads to an 80% decrease in the abundance of Faecalibacterium prausnitzii and a fivefold increase in Fusobacterium nucleatum. The latter is closely related to the progression of colorectal cancer.

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Youdaoplaceholder0 Chapter Five Future Prospects: The vast Ocean of Glyco-based Drugs ?

Youdaoplaceholder0 5.1 The Glycolic Revolution in Precision Medicine ?

Individualized treatment strategies based on tumor metabolic heterogeneity are emerging. The "Mannose Sensitivity Score" (MSS) model developed by the Broad Institute in the United States can predict the response probability of patients to mannose by detecting the expression level of GLUT1, hexokinase activity and PMI mutation status in tumor tissues. In the design of Phase II clinical trials, pancreatic cancer patients with an MSS score of ≥75% will be given priority for inclusion to improve the treatment response rate.

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Youdaoplaceholder0 5.2 Cross-border fusion of sugar Engineering drugs ?

Frontier research is no longer satisfied with the single application of natural mannose. The MIT team has designed a "mannose-paclitaxel" conjugate, which takes advantage of the high uptake of mannose by tumor cells to achieve targeted delivery of chemotherapy drugs. In breast cancer models, the tumor-killing efficacy of this conjugate was three times that of traditional paclitaxel, and its cardiotoxicity was reduced by 60%. Another breakthrough comes from Shanghai Jiao Tong University: by combining mannose with the photosensitizer Ce6, a "sugar-based photodynamic therapy" that can be activated by near-infrared light has been developed, demonstrating potential in deep tumor ablation.

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Youdaoplaceholder0 Conclusion: The "sweet molecule" rewriting the anti-cancer rules ?

The anti-cancer journey of mannose is a brilliant spark sparked by the collision of basic science and clinical needs. From metabolic intervention to immune regulation, from monotherapy to combination regimens, this sugar molecule is breaking down the tumor defense line with multi-dimensional attack strategies. Although the commercialization path still faces challenges such as dose optimization, drug resistance mechanisms, and regulatory norms, the scientific community holds high hopes for it - as Nobel laureate James Watson put it, "The essence of cancer is genomic disorder, and mannoglucose teaches us that metabolic intervention may restore order." Driven by the dual wheels of precision medicine and synthetic biology, this "sweet revolution" may usher in a new era of cancer treatment.