news

한어Русский языкEnglishFrançaisIndonesianSanskrit日本語DeutschPortuguêsΕλληνικάespañolItalianoSuomalainenLatina

For a long time, people have treated tumors through strategies such as surgery, chemotherapy, radiotherapy and targeted drugs, focusing mainly on the direct killing of tumor cells, which inevitably brings about problems such as tumor resistance and treatment side effects.

In recent years, immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapy have mobilized the immune system to identify and eliminate tumor cells, showing the potential to change the treatment landscape of malignant tumors.

Immune checkpoint agonists in immunotherapy exert anti-tumor effects by enhancing the activity of immune cells and activating the immune system.

Currently, immune agonists targeting pathways such as GITR, OX40 and STING are in clinical trials. However, existing immune agonists have problems such as over-activation of the immune system, large individual differences among different patients, and high difficulty in developing precision therapeutic drugs, resulting in a low proportion of patients benefiting from clinical treatment.

Metabolic abnormalities are a common and key feature of tumor occurrence and development. Currently, some anti-tumor metabolic drugs can inhibit tumor growth to a certain extent by regulating abnormal tumor metabolic pathways. However, existing metabolic therapeutic drugs have problems such as short half-life in vivo, obvious off-target effects, and easy interference with normal cell metabolism.

Recently, Professor Ling Daishun and Researcher Li Fangyuan from Shanghai Jiao Tong University collaborated for the first time to focus on broad-spectrum tumor metabolic markers as metabolic immune checkpoints and proposed a new tumor metabolic activation immunotherapy strategy.

They innovatively synthesized a FeMoO4 life system catalyst that mimics the iron and tetrahedral molybdenum atom conformation in xanthine oxidoreductase (XOR), called an "artificial metabolic enzyme."

Simply put, "artificial metabolic enzymes" catalyze and regulate the metabolism of tumor cells themselves, producing a new immune activation signal (broad-spectrum metabolic immune checkpoints), thereby precisely activating neighboring immune cells, enabling them to specifically identify and attack tumor cells.

In layman's terms, it can be understood as: let the tumor cells themselves ignite the "spark" and then achieve the effect of "spreading a prairie fire".

Figure 丨 Group photo of the authors of the paper, from left to right: Hu Xi, Li Fangyuan and Ling Daishun (Source: the team)

This study focuses on the artificial simulation of natural metabolic enzymes and the regulation of tumor-immune cell interactions, and proposes a new immune detection and stimulation strategy, providing a new strategy based on chemical biology for the precision treatment of tumors and other major immune and metabolic-related diseases.

Recently, a related paper titled “An artificial metabzyme for tumour-cell-specific metabolic therapy” was published in Nature Nanotechnology[1].

Dr. Hu Xi (currently a professor and doctoral supervisor at Anhui University of Chinese Medicine), Dr. Zhang Bo, and master's students Zhang Miao and Liang Wenshi from Shanghai Jiao Tong University are the co-first authors, and Professor Ling Daishun and Researcher Li Fangyuan from Shanghai Jiao Tong University are the co-corresponding authors.

Figure 丨 Related papers (Source: Nature Nanotechnology)

The catalytic process of enzymes in living systems is closely related to the regulation of living metabolism. Metabolic abnormalities can cause the occurrence, development and evolution of diseases.

Therefore, in theory, therapeutic interventions for various major diseases related to metabolic abnormalities (including tumors, cardiovascular and cerebrovascular diseases, gout, and diabetes, etc.) are expected to be reshaped and corrected through targeted designed artificial metabolic enzymes.

Ling Daishun said: "Based on this research, we will continue to focus on disease metabolic pathways and key metabolites, and systematically synthesize a series of artificial metabolic enzymes that specifically regulate metabolic pathways or metabolites. This may be the key to achieving precise metabolic regulation of diseases in the future."

Figure 丨 Schematic diagram of artificial metabolic enzymes used for tumor cell-specific metabolic activation immunotherapy (Source: Nature Nanotechnology)

It is reported that this study was inspired by clinical practice and began in 2020. At that time, the research team found that there were clinical reports that low expression of natural metabolic enzymes (such as XOR) in the human body was positively correlated with poor prognosis of tumor patients.

So Ling Daishun boldly hypothesized, is it possible to use abnormal tumor metabolic pathways or metabolites as key targets, develop an artificial metabolic enzyme, and thus achieve precise tumor-specific metabolic treatment?

Based on this, researchers tried to understand the mechanism of action of natural metabolic enzymes in the human body from a molecular level and carried out research on artificial simulation of anabolic enzymes.

The metal active center of natural metabolic enzymes is a key element of enzyme-catalyzed reactions. In the research process, XOR was used as the first reference model. In order to effectively construct the Mo and Fe cofactor structures that mimic XOR, the efficient metal single atom doping of artificial enzyme systems posed a great challenge.

Because heterogeneous nucleation is very easy to occur during the single-atom doping process of heterogeneous metals, which usually leads to a low loading rate of metal single atoms.

Based on a study published in JACS in 2020 by the team [2], they found that the solvothermal method can be used to regulate the hydrolysis rate of the molybdenum oxide surface and create a large number of defect sites by regulating the defect sites on the molybdenum oxide surface.

Therefore, the researchers proposed to obtain a large number of molybdenum defect sites by controlling the dissolution of the molybdenum oxide surface. These defect sites can serve as adsorption and anchoring sites for heterogeneous iron single atoms, thereby achieving efficient iron single atom doping.

Moreover, the entire preparation process can be completed in one step, without the need for conventional high-temperature calcination or complicated preparation steps. They named this technology "dissolution-adsorption-anchoring" single-atom interface engineering technology.

It is worth noting that in this study, the researchers increased the single-atom doping ratio to more than 20wt% by regulating surface defects and the adsorption and anchoring process of single atoms.

"In previous studies, it was quite difficult to achieve a single-atom doping ratio of more than 5%. We controlled the dissolution of the molybdenum oxide surface to obtain a large number of molybdenum defect sites, which served as adsorption and anchoring sites for heterogeneous iron single atoms, and successfully achieved efficient doping of metal single atoms," said Hu Xi.

Finally, they achieved lattice reconstruction by controlling iron doping and prepared an artificial metabolic enzyme that can accurately simulate the conformation of iron and tetrahedral molybdenum atoms in XOR. This artificial metabolic enzyme can simulate the catalytic process of XOR, that is, catalyzing xanthine to uric acid.

Figure 丨 Design and construction of FeMoO4 artificial metabolic enzyme (Source: Nature Nanotechnology)

The researchers constructed an artificial metabolic enzyme through single-atom interface engineering technology and used spatial metabolomics to analyze tumor-related metabolites, proving that it can catalyze and mediate the metabolic process of tumor cells from xanthine to uric acid.

Li Fangyuan said: "We found that the uric acid molecule, a metabolite of tumor cells mediated by artificial metabolic enzymes, can serve as a 'localization and activation signal' to induce nearby macrophages to polarize to the M1 phenotype and secrete IL-1β, allowing macrophages to recognize and engulf tumor cells.

At the same time, uric acid and the pro-inflammatory cytokine IL-1β can enhance the activity of immune cells such as dendritic cells and T cells, thereby significantly stimulating anti-tumor immune responses. "

Hu Xi is the first doctoral student recruited by Professor Ling Daishun after he returned to China to teach. After graduating with a doctorate, she has accumulated several years of experience in postdoctoral, visiting and clinical work. She is currently a professor, doctoral supervisor, and project leader at Anhui University of Traditional Chinese Medicine, dedicated to the research of bionic nanomaterials and disease metabolic treatment.

Based on this research, the team believes that more natural enzyme abnormal metabolic targets can be explored in the future, which is expected to revolutionize the treatment paradigm for difficult diseases related to metabolic abnormalities.

Li Fangyuan gave an example, saying: "In the future, we can accurately simulate more natural metabolic enzymes. Metabolic abnormalities are common in many disease systems such as tumors, nervous systems, and autoimmune diseases. Therefore, precise metabolic regulation of diseases based on artificial metabolic enzymes has broad application prospects."

In the next stage of research, the research team will further explore the impact of artificial metabolic enzymes on the specific catalytic processes of various cells and their key metabolites at the molecular level, as well as their effects on the regulation of life functions. At the same time, it will demonstrate the therapeutic potential for various major diseases.

This research received advice and help from Academician Fan Chunhai of Shanghai Jiao Tong University. In the future, the research will rely on the platform of the National Science Center for Translational Medicine of Shanghai Jiao Tong University to conduct clinical translation research on this achievement.

In addition, the research team also plans to further cross-disciplinary cooperation with other disciplines and independently build a synchrotron radiation in-situ detection device to observe the structural evolution and reaction mechanism of artificial metabolic enzymes during the catalytic process, further explain the metabolic and immune regulation mechanisms in principle, and improve scientific hypotheses.

"In the future, perhaps we can create a series of artificial metabolic enzymes that specifically regulate metabolic pathways and metabolites for abnormal metabolic pathways and targets of various diseases, and create a new paradigm of precision metabolic treatment driven by chemical biology," said Ling Daishun.

References:

1.Hu, X., Zhang, B., Zhang, M. et al. An artificial metabzyme for tumour-cell-specific metabolic therapy. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01733-y

2.Hu, X. et al. Biodegradation-Mediated Enzymatic Activity-Tunable Molybdenum Oxide Nanourchins for Tumor-Specific Cascade Catalytic Therapy. Journal of the American Chemical Society 2020, 142, 1636−1644. https://pubs.acs.org/doi/10.1021/jacs.9b13586

Operation/Layout: He Chenlong

01/

02/

03/

04/

05/