The connection between a growth-regulating protein, a familiar waste product, and the immune cells surrounding a tumor.

A tumor changes the tissue around it as it grows. Cells consume nutrients, release metabolites, and alter the chemical conditions their neighbors must live in. Those changes can influence whether immune cells remain effective and whether cancer cells survive. Ammonia is one molecule through which this relationship becomes visible.

Usually associated with the disposal of nitrogen, ammonia can also become a usable resource. Some cancer cells recover its nitrogen for growth. At the same time, ammonia can interfere with the immune cells attempting to destroy them. Its local concentration can therefore affect both sides of the encounter.

MYC sits near the beginning of this story. A protein that helps regulate gene expression, MYC coordinates processes involved in cell growth and metabolism. When its activity becomes excessive, the resulting changes can extend beyond the cancer cell itself. One consequence can be increased ammonia production. [1]

The Metabolic Cost of Growth

Building a new cell requires a steady supply of materials. Glutamine contributes to that supply, carrying carbon and nitrogen that cells can use in metabolism and biosynthesis. MYC can increase glutamine use, including activity along a pathway involving the enzyme glutaminase. This enzyme converts glutamine into glutamate and releases ammonia in the process. [1] [2]

That gives the relationship a clear forward direction: increased MYC activity can drive glutamine metabolism that produces ammonia. Whether ammonia then accumulates depends on how quickly it is reused, removed, or carried away.

The urea cycle is part of the body’s nitrogen-disposal machinery. Reduced activity of components of this pathway can contribute to ammonia accumulation in some tumors. This has been linked to impaired immune function in colorectal cancer, but the metabolic changes vary between cancers; MYC cannot be assumed to switch off the urea cycle in every case. [3]

MYC can also increase an enzyme called glutamine synthetase. Despite its similar name, it performs a different job from glutaminase: it captures ammonia and combines it with glutamate to make glutamine. In this way, MYC can support both the production of ammonia and its recovery into a usable nutrient. Local ammonia levels reflect the balance between these processes. [4]

Waste That Becomes a Resource

For a growing cancer cell, nitrogen is valuable. It is needed to make amino acids and the building blocks of DNA and RNA. Recovering nitrogen that would otherwise be lost can help support this demand.

Breast cancer cells, for example, can incorporate ammonia nitrogen into glutamate through the enzyme glutamate dehydrogenase. That nitrogen can then pass into other amino acids. The ammonia enters a chain of metabolic reactions that makes it useful for building cellular material. [5] Glutamine made through ammonia assimilation can also support nucleotide synthesis and survival when the external glutamine supply is limited. [4]

Ammonia can influence autophagy as well. This is the internal recycling process through which cells break down and recover their own components. Under some conditions, an ammonia-associated autophagy response helps cells tolerate stress. Its effects depend on concentration and cellular circumstances: an exposure that supports adaptation in one setting can disrupt function in another. [6] [7]

Ammonia therefore occupies an unusual position in tumor biology. It can be a by-product, a source of nitrogen, and an influence on how cells respond to their surroundings. Which role dominates depends on the cell and the conditions around it.

When Immune Cells Lose Their Killing Power

The same chemical environment can affect neighboring cells very differently. While a cancer cell may reuse ammonia, an immune cell may struggle to function in its presence. In colorectal cancer models, ammonia exposure impaired T-cell proliferation and activity and increased features associated with exhaustion. [3]

Ammonia can also interfere with the machinery used to kill a target. Cytotoxic immune cells rely on specialized compartments that store the proteins needed for an effective attack. One of those proteins is perforin. Ammonia can make these normally acidic compartments less acidic, reducing the amount of mature perforin available. This has been linked to weaker killing by natural killer cells and engineered CAR-T cells in laboratory experiments. [8]

An affected immune cell may still recognize a cancer cell and make contact with it. The failure occurs further along, when it needs to deliver an effective attack. Ammonia can thus weaken immune protection without making the tumor literally invisible. The pH change involved occurs inside cellular compartments and should be distinguished from the acidity of the surrounding tissue. [8]

Regulatory T cells add another layer. These cells restrain immune responses. In liver cancer, they have been shown to adapt to ammonia and increase their suppressive activity. An ammonia-rich environment can therefore disadvantage some immune cells while favoring others, shifting the local balance away from effective tumor killing. [9]

The Chicken-and-Egg Connection

MYC can help create an ammonia-rich environment. The possibility that ammonia can influence MYC in return makes the relationship more complicated.

The reverse connection is less certain. In one liver cancer cell line, lower ammonia exposure increased MYC protein alongside an autophagy response, whereas higher exposures produced a declining MYC response. This suggests that ammonia can affect MYC under particular conditions. A self-sustaining MYC–ammonia loop, however, has not been established, and these observations do not show that ammonia starts a cancer. [7]

The distinction between starting and sustaining a process helps make sense of the apparent chicken-and-egg problem. A genetic change could activate MYC first. The resulting metabolic changes might then help maintain conditions favorable to the tumor. In another setting, impaired ammonia disposal could develop independently and change the environment encountered by cancer and immune cells.

There may therefore be more than one starting point. A tumor and its surroundings can influence each other over time, even when the original trigger acted in only one direction. The important uncertainty is how strongly these interactions reinforce one another in a particular cancer.

Why the Relationship Matters

The MYC–ammonia connection broadens the way we think about a growth-promoting protein. Its consequences can include changes to the shared environment in which both cancer cells and immune cells operate. A metabolic pathway inside one cell may affect the ability of another cell to survive or attack.

This also gives ammonia potential relevance as a treatment target. Reducing a harmful ammonia burden could, in principle, relieve some of the pressure on immune cells even if MYC activity remained high. Ammonia clearance has improved immune activity and tumor outcomes in colorectal cancer mouse models, but a clinical benefit from targeting this mechanism has not been established in people. [3]

The broader biological lesson is that a tumor’s waste can become part of the conditions that support its persistence. MYC may help generate that waste, cancer cells may recover its nitrogen, and immune cells may bear some of its cost. Understanding these connections places the cancer cell within the environment it helps create.

References

1. Wise DR et al. (2008). MYC regulation of glutaminolysis and glutamine dependence. ( https://pubmed.ncbi.nlm.nih.gov/19033189/) PNAS.

2. Gao P et al. (2009). MYC, miR-23a/b, and mitochondrial glutaminase. ( https://pubmed.ncbi.nlm.nih.gov/19219026/) Nature.

3. Bell HN et al. (2023). Microenvironmental ammonia and T-cell exhaustion in colorectal cancer. ( https://doi.org/10.1016/j.cmet.2022.11.013) Cell Metabolism.

4. Bott AJ et al. (2015). MYC induction of glutamine synthetase through promoter demethylation. ( https://pubmed.ncbi.nlm.nih.gov/26603296/) Cell Metabolism.

5. Spinelli JB et al. (2017). Ammonia recycling through glutamate dehydrogenase in breast cancer. ( https://pubmed.ncbi.nlm.nih.gov/29025995/) Science.

6. Eng CH et al. (2010). Glutaminolysis-derived ammonia as a regulator of autophagy. ( https://pubmed.ncbi.nlm.nih.gov/20424262/) Science Signaling.

7. Sergio S et al. (2025). β-catenin/c-MYC and autophagy responses to different ammonia concentrations. ( https://doi.org/10.1002/adbi.202400408) Advanced Biology.

8. Domagala J et al. (2025). Ammonia, mature perforin, and impaired NK- and T-cell antitumor activity. ( https://doi.org/10.1158/0008-5472.CAN-24-0749) Cancer Research.

9. Gu J et al. (2026). Tumor-produced ammonia metabolism by regulatory T cells. ( https://pubmed.ncbi.nlm.nih.gov/41448182/) Cell.