To divide at an accelerated rate, tumor cells must build new membranes and repair their cellular components, which requires large amounts of energy and raw materials. However, recent research has revealed something more profound: the metabolic changes that occur in tumors do not simply fuel their growth—they may also help cancer hide from the immune system.
In other words, tumors do not use nutrients only to survive. They can also reshape their surroundings by producing substances that weaken immune cells, promote immunosuppression, and reduce the effectiveness of certain treatments.
Cancer reorganizes its production and consumption pathways
Normal cells carefully regulate their use of glucose, fats, and amino acids according to their needs, allowing them to make efficient use of the available resources. This is part of what is known as metabolic balance.
Cancer cells, however, often reorganize multiple metabolic pathways to support rapid proliferation and adapt to unfavorable conditions, such as low oxygen or limited nutrients. As a result, they consume larger quantities of molecules and process them at a faster rate.
A well-known example is the Warburg effect, in which tumor cells take up large amounts of glucose to support their energy needs. But cancer metabolism goes far beyond glucose consumption.
Cancer cells can also modify different metabolic pathways to produce the biomolecules that serve as building blocks for growth, including proteins, lipids, and nucleic acids. At the same time, these pathways generate molecules capable of changing the behavior of nearby cells and tissues, including immune cells.
In some tumors, increased glucose metabolism has been associated with lower infiltration by T cells, specialized immune cells that recognize and attack malignant cells. At first, this may lead us to assume that cancer simply consumes all the available glucose and leaves immune cells without enough fuel. In reality, the process is more complex: tumor metabolism also changes the signals released into the surrounding environment, making an effective immune attack less likely.
For example, elevated glucose metabolism may increase the expression of PD-L1, a molecule that acts as an immune brake, and stimulate the release of factors that attract suppressive cells. In patients with triple-negative breast cancer, high expression of LDHA—an enzyme involved in glucose metabolism that promotes lactate production—has been associated with poorer clinical outcomes.
When lactate accumulates, it can contribute to the acidification of the tumor environment. This acidic setting may impair the proliferation and activity of cytotoxic T cells and natural killer cells, two immune populations that are essential for recognizing and destroying malignant cells.
Lactate may also favor the presence and activity of regulatory T cells. Under normal conditions, these cells help prevent excessive immune reactions. In cancer, however, they can become a protective shield for the tumor.
In addition, some tumor-associated macrophages respond to lactate-derived signals by adopting a state similar to the so-called M2-like profile, which is associated with tissue repair, immunosuppression, and tumor progression.
Overall, excessive glucose metabolism and the substances it produces can help the tumor resist immune attack, allowing it to grow and potentially spread more easily.
Mitochondria also send signals
The tricarboxylic acid cycle, also known as the Krebs cycle, produces energy and generates metabolites with important regulatory functions.
When certain enzymes involved in this cycle are altered, molecules such as fumarate, succinate, or 2-hydroxyglutarate may accumulate. These metabolites can enter immune cells and interfere with their normal function.
For example, D-2-hydroxyglutarate produced by some tumors can inhibit T-cell proliferation and reduce the production of interferon gamma, an important molecule involved in coordinating immune responses.
Fumarate may also directly interfere with proteins involved in signaling through the T-cell receptor, the structure that allows T cells to recognize tumor targets and initiate their destruction.
Fats can build the tumor and block immunity
Cancer cells need lipids to form new membranes, store energy, and produce signaling molecules. For this reason, many tumors increase either fatty acid oxidation or lipid synthesis.
In some cancers, increased fatty acid oxidation has been linked to higher expression of CD47, a molecule that sends macrophages a “do not eat me” signal. This reduces the phagocytosis, or engulfment, of malignant cells. It may also contribute to resistance against cell death induced by interferon gamma.
Fatty acid synthesis is largely controlled by an enzyme called FASN. High FASN expression has been associated with more advanced disease and reduced T-cell infiltration in some cancers. Lipids that accumulate within the tumor microenvironment can also be taken up by lymphocytes and interfere with their activity.
Increased FASN activity may also promote the formation of intracellular lipid droplets associated with COX-2 and the production of prostaglandin E2.
Prostaglandin E2 can limit the function of dendritic cells, natural killer cells, and T cells. It may also increase PD-L1 expression in myeloid cells, further strengthening the tumor’s immunosuppressive environment.
ATP and Adenosine: two opposing messages
Nucleotides also participate in the communication between tumors and the immune system.
When a stressed or dying tumor cell releases ATP into the extracellular environment, this molecule can act as a danger signal. Extracellular ATP attracts dendritic cells and can help initiate an immune response.
However, tumors can rapidly convert ATP into adenosine through the activity of the enzymes CD39 and CD73.
Adenosine produces the opposite effect. It inhibits immune effector cells, favors regulatory populations, and helps create an immunosuppressive environment.
The balance between ATP and adenosine can therefore influence whether tumor cell death successfully activates the immune system or whether that immune signal is ultimately neutralized.
This pathway is already being investigated as a therapeutic target. Inhibitors of CD39, CD73, and adenosine receptors have shown the ability to improve antitumor immunity in preclinical models, and some are being evaluated in combination with immune checkpoint inhibitors.
Amino Acids: competition for essential resources
Glutamine is an amino acid that is heavily used by both cancer cells and immune cells.
In some tumors, excessive glutamine consumption by malignant cells may impair dendritic-cell function and contribute to a tumor environment with limited T-cell infiltration.
Experimental strategies have shown that selectively blocking glutamine metabolism in tumors may reduce suppressive immune cells, promote macrophages with more immune-stimulating characteristics, and help T cells maintain their activity.
The main challenge is achieving sufficient selectivity, because lymphocytes also depend on glutamine to perform their functions.
Methionine provides another example. Tumor cells may express high levels of transporters that capture this amino acid, placing them in direct competition with T cells. Reduced methionine availability can alter epigenetic regulation and weaken the signaling processes required for effective T-cell function.
In the case of tryptophan, immunosuppression is mainly associated with its conversion into metabolites such as kynurenine through enzymes including IDO1 and TDO.
Kynurenine can inhibit lymphocytes and promote regulatory T cells. Although this pathway initially appeared to be a promising therapeutic target, a phase III clinical trial combining the IDO1 inhibitor epacadostat with pembrolizumab did not demonstrate greater benefit than pembrolizumab alone.
This result is an important reminder that metabolic pathways rarely operate in isolation and that tumors may activate alternative mechanisms when one pathway is blocked.
Figure 1. Tumor metabolism can reshape the immune microenvironment through increased glucose and lactate use, altered lipid metabolism, and competition for amino acids, weakening antitumor immune cells while favoring immunosuppressive populations.
Can cancer metabolism be blocked without damaging immunity?
Targeting tumor metabolism is an attractive strategy, but it presents a major challenge: many of the same metabolic pathways are also essential for healthy cells and for the immune system itself.
Broadly inhibiting glucose use, glutamine metabolism, or lipid synthesis might weaken the tumor, but it could also affect neurons, muscles, the liver, or lymphocytes.
For this reason, the goal should not simply be to “starve the cancer.” Instead, researchers aim to identify specific metabolic vulnerabilities and direct treatment preferentially toward malignant cells.
Proposed strategies include delivery systems designed to recognize receptors that are more abundant on tumor cells. It will also be important to analyze biopsies before and after treatment to understand how tumor metabolism changes and how those changes influence immune-cell behavior.
Future research will need to determine which metabolic pathway dominates in each tumor, which patients are most likely to benefit, and how metabolic inhibitors should be combined with immunotherapy, radiotherapy, or other treatments.
Researchers will also need to consider factors such as obesity, diabetes, the microbiome, and previous therapies, all of which can influence both metabolism and the immune response.
Main reference:
De Martino, M., Rathmell, J. C., Galluzzi, L., & Vanpouille-Box, C. (2024). Cancer cell metabolism and antitumour immunity. Nature reviews. Immunology, 24(9), 654–669. https://doi.org/10.1038/s41577-024-01026-4
Other references:
Zhu, Y., Zhou, Z., Du, X., Lin, X., Liang, Z. M., Chen, S., Sun, Y., Wang, Y., Na, Z., Wu, Z., Zhong, J., Han, B., Zhu, X., Fu, W., Li, H., Luo, M. L., & Hu, H. (2025). Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion. Cancer cell, 43(6), 1045–1060.e7. https://doi.org/10.1016/j.ccell.2025.03.015
Kroemer, G., & Pouyssegur, J. (2008). Tumor cell metabolism: cancer’s Achilles’ heel. Cancer cell, 13(6), 472–482. https://doi.org/10.1016/j.ccr.2008.05.005
