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New Perspectives in Cancer and Immunotherapy Research: The Potential of Metabolic Pathways in Oncology

08 August 2025

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Metabolic alterations in cancer cells represent one of the hallmarks of malignancy. However, when attempting to treat cancer through metabolic modulation, we must simultaneously consider the metabolic pathways of immune cells. As our understanding of immunometabolism deepens, it becomes evident that by regulating metabolic pathways, we can not only directly inhibit tumor cell growth but also enhance immune cell function, thereby achieving more effective anti-cancer responses.

Let's explore the intricate connections between tumor metabolism and immunotherapy, analyzing current research progress and challenges across four key metabolic battlegrounds:

· amino acids,

· nucleosides,

· glycolysis, and

· microbiome.

I. Amino Acid Metabolism: Tumor's "Nutritional Competition"

Amino acids serve as fundamental building blocks of proteins and crucial participants in cellular metabolism. Within the tumor microenvironment, amino acid metabolic pathways undergo significant alterations. For instance, indoleamine 2,3-dioxygenase 1 (IDO1) expression increases in tumor cells, dendritic cells, and macrophages; glutaminase 1 (GLS1) expression is elevated in tumor cells, catalyzing the conversion of glutamine to glutamate. IDO1 catalyzes the conversion of tryptophan to kynurenine, resulting in tryptophan depletion and kynurenine accumulation [1]. These changes not only affect tumor cell growth and proliferation but also significantly impact immune cell function.

Figure 1. Targeting amino acid metabolism to enhance cancer immunotherapy [1].

Tryptophan Metabolism: A Key to Immunosuppression

Tryptophan, an essential amino acid, plays a critical role in tumor immunity. Key enzymes in tryptophan metabolism include IDO1 and tryptophan 2,3-dioxygenase (TDO), which metabolize tryptophan to kynurenine. Kynurenine accumulates in the tumor microenvironment [2], activating the aryl hydrocarbon receptor (AHR) and inducing regulatory T cell (Treg) differentiation while promoting myeloid-derived suppressor cell (MDSC) infiltration, thereby suppressing anti-tumor immune responses.

Research Targets and Inhibitors: Epacadostat, 680C91 and LM10, have demonstrated promising anti-tumor effects in clinical trials.

Figure 2. AmBeed product details, all in stock.

· Glutamine Metabolism: The Tumor Cell's "Power Plant"

Glutamine is one of the most abundant amino acids in cells and serves as a vital energy source for tumor cells. Tumor cells upregulate glutamine transporters to facilitate substantial glutamine uptake, metabolizing it to α-ketoglutarate, which enters the tricarboxylic acid (TCA) cycle, providing energy and biosynthetic precursors for tumor cell proliferation.

Research Targets and Therapeutics: Inhibition of glutamine-to-glutamate conversion represents a promising approach. Glutaminase inhibitors such as CB-839 and IPN60090 have demonstrated favourable tolerability in clinical trials and enhanced the efficacy of immune checkpoint inhibitors in tumor models.

Figure 3. AmBeed product details.

II. Nucleoside Metabolism: The Immunosuppressive Effects of Adenosine

Nucleosides, beyond being components of DNA and RNA, play crucial roles in cellular signalling. Adenosine, a significant nucleoside, is closely associated with immunosuppression when accumulating in the tumor microenvironment. Adenosine generation primarily occurs through extracellular nucleotide metabolism pathways, including enzymatic reactions catalyzed by CD39 and CD73. CD39 converts ATP to AMP, which CD73 subsequently converts to adenosine. Adenosine inhibits T cell and natural killer (NK) cell function by activating A2A and A2B receptors while promoting differentiation of immunosuppressive M2 macrophages and regulatory T cells [3].

Figure 4. Targeting nucleoside metabolism in anti-tumor immunity

Research Targets and Therapeutics: CD39 and CD73 inhibitors, such as oleclumab (MEDI9447) and quemliclustat (AB680), have shown improved progression-free survival when combined with PD-L1 inhibitors. A2A and A2B receptor antagonists, including etrumadenant (AB928) and ciforadenant, have also been developed. Etrumadenant has demonstrated good tolerability and anti-tumor effects in studies. These inhibitors enhance anti-tumor immune responses by blocking adenosine-receptor binding, thereby restoring T cell and NK cell function.

Figure 5. AmBeed product details, all in stcok.

III. Glycolysis and the Dual Role of Lactate

Glycolysis represents a critical pathway in cellular energy metabolism. Cancer cells enhance glycolysis to meet their rapid proliferation energy demands. This metabolic pattern, known as the "Warburg effect," describes cancer cells' preference for glycolysis to produce lactate even under aerobic conditions. Lactate accumulation not only leads to acidification of the tumor microenvironment but also exerts inhibitory effects on immune cell function. Lactate can suppress immune cell function through multiple mechanisms. For instance, it can reduce phosphoenolpyruvate (PEP) levels in T cells, thereby inhibiting the Ca²⁺-NFAT signalling pathway. Additionally, it can enhance the TGF-β signalling pathway by activating lactylation of the MOESIN protein in T cells, promoting regulatory T cell accumulation [4].

Figure 6. Metabolic interventions in glycolysis and mitochondrial respiration.

Research Targets and Inhibitors: Inhibiting lactate production and transport represents an important strategy for enhancing anti-tumor immunity. Lactate dehydrogenase (LDHA) inhibitors such as GSK2837808A enhance anti-tumor immune responses by reducing lactate production. MCT1 and MCT4 inhibitors, including AZD3965 and AR-C155858, reduce lactate accumulation in the tumor microenvironment by blocking lactate efflux from cells.

Figure 7. AmBeed product details, all in stock.

IV. Microbial Metabolism: Synergistic Effects of Gut Microbiota and Immunotherapy

At the frontier of cancer immunotherapy, the metabolic regulation of gut microbiota is emerging as a research hotspot. Through their rich metabolic products, intestinal microbes not only influence host digestion and nutrient absorption but also profoundly modulate immune system function. Increasing evidence suggests that gut microbiota composition and metabolites are closely associated with cancer patients' responses to immunotherapy, providing new strategies and targets for immunotherapeutic approaches. Microbial metabolites such as short-chain fatty acids (SCFAs), bile acids, and tryptophan metabolites play significant roles in regulating immune cell function. For example, SCFAs influence immune responses by modulating T cell differentiation and function. Bile acids regulate immune cell function by activating the farnesoid X receptor (FXR).

Tryptophan metabolites, such as indole-3-propionic acid (I-3-P), enhance anti-tumor immune responses by activating AHR [5].

Figure 8. Impact of microbiota, nutrition, and fasting on the tumor microenvirnment.

Research Targets and Modulators: Microbial metabolite supplements, such as urolithin A, enhance immune cell function by activating autophagy. Bile acid regulators, such as ursodeoxycholic acid (UDCA), enhance immunotherapy efficacy by modulating bile acid metabolism.

Conclusion

Figure 9. Regulation of metabolic pathways in tumors.

References

[1]Trefny, M.P., Kroemer, G., Zitvogel, L. et al. Metabolites as agents and targets for cancer immunotherapy. Nat Rev Drug Discov (2025).

[2]Xue, C. et al. Tryptophan metabolism in health and disease. Cell Metab. 35, 1304–1326 (2023).

[3]Bendell, J. et al. First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors. Cancer Immunol., Immunother. 72, 2443–2458 (2023).

[4]Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

[5]Gu, J. et al. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signalling in regulatory T cells. Cell Rep. 39, 110986 (2022).

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