MYC and Ammonia

Cancer metabolism / Research perspective

MYC and Ammonia: When Cancer’s Waste Talks Back

A possible feedback loop connects an oncogene, nitrogen metabolism, and immune suppression. Could interrupting it expose a new cancer vulnerability?

Imagine a cancer cell changing its surroundings as it grows. The nutrients it consumes leave chemical traces. Some become building materials for neighboring cells. Others interfere with the immune cells trying to destroy the tumor. A molecule that begins as metabolic waste can become part of the environment that helps the cancer persist.

Ammonia brings this possibility into focus. Its connection to MYC, a protein that regulates growth and metabolism, raises a provocative question: does MYC create the ammonia-rich environment, or can ammonia help sustain MYC? The answer may involve both directions—but the evidence for them is unequal.

A tumor’s metabolic output may help maintain the conditions that support it. If ammonia participates in that maintenance, clearing it could matter even when MYC itself remains difficult to inhibit.

This article examines experimental findings and research proposals. The ammonia-targeting approaches discussed here have not established clinical benefit for treating cancer in people.

Part I / The nitrogen balance

How MYC Can Increase Ammonia Production

MYC helps coordinate the supply of nutrients needed for growth. In a foundational study, reducing MYC in a human glioma cell line lowered glutamine consumption and ammonia production. This provides experimental evidence for a forward connection: MYC can drive metabolism that releases ammonia. [Wise et al., 2008]

One route runs through glutaminase, or GLS, which converts glutamine into glutamate and releases ammonia. Researchers subsequently showed that MYC can increase GLS expression by repressing microRNAs that normally restrain it. [Gao et al., 2009]

MYC activity → increased glutamine use → ammonia production

Production, however, is only one side of the balance. Local ammonia also depends on reassimilation, disposal, and movement between cells and tissues. A tumor that produces ammonia rapidly will not necessarily accumulate it if removal keeps pace.

The urea-cycle connection needs qualification. Impaired ammonia disposal can contribute to accumulation, as demonstrated in colorectal cancer research involving HNF4α and the urea-cycle enzyme OTC. That finding does not establish a universal sequence in which MYC switches off the urea cycle. [Bell et al., 2023]

MYC can also increase glutamine synthetase, or GS, which captures ammonia and combines it with glutamate to make glutamine. In the studied models, this supported survival when glutamine was scarce and supplied nucleotide synthesis. MYC therefore has the capacity to promote both ammonia-producing and ammonia-consuming pathways. Their relative activity matters more than the MYC label alone. [Bott et al., 2015]

Throughout this article, “ammonia” refers broadly to the interconverting NH₃/NH₄⁺ pool. Their relative proportions depend on pH; the two forms should be distinguished when interpreting experiments.

Waste That Can Be Reused

Recovering Nitrogen

Isotope-tracing experiments showed that breast cancer cells can incorporate ammonia nitrogen into glutamate through glutamate dehydrogenase, then transfer it into other amino acids. This recycling supported tumor biomass. Describing ammonia as being “turned into DNA” skips the metabolic intermediates that make nitrogen usable. [Spinelli et al., 2017]

Adjusting Cell Recycling

Ammonia released by glutamine metabolism can regulate autophagy, the process through which cells recycle internal components. In experimental systems, this response helped cells tolerate stress. Its effect depends on exposure and cellular context; ammonia is not an unlimited growth resource. [Eng et al., 2010]

Part II / The immune cost

An Environment That Weakens Tumor Killing

A metabolite useful to a cancer cell can be harmful to an immune cell beside it. Colorectal cancer experiments linked ammonia exposure to impaired T-cell proliferation and function, with increased exhaustion-associated features. This gives ammonia a possible role in maintaining immune suppression. [Bell et al., 2023]

A separate study identified a more specific failure in the killing machinery. Ammonia increased pH inside acidic cellular compartments and reduced mature perforin, a protein required for effective cytotoxic attack. NK cells and engineered CAR-T cells consequently killed cancer cells less effectively in vitro. [Domagala et al., 2025]

Ammonia exposure → less acidic secretory compartments → less mature perforin → weaker killing

The immune cell may still recognize and contact its target while delivering a less effective attack. These findings also concern pH inside cellular compartments; they do not show that the whole tumor becomes alkaline. [Domagala et al., 2025]

Different immune cells can respond differently. A liver cancer study published in Cell in 2026 found that regulatory T cells could adapt to ammonia and strengthen their suppressive function. Together, these observations suggest a local imbalance: reduced activity of tumor-killing cells alongside support for cells that restrain immunity. [Gu et al., 2026]

Part III / The chicken-and-egg question

Can Ammonia Send a Signal Back to MYC?

There is an experimental clue. In a 2025 study using Huh7 liver cancer cells, a lower ammonium chloride exposure increased c-MYC protein and active β-catenin, alongside an autophagy response. Higher exposures produced a declining MYC response. Manipulating MYC supported its involvement in the autophagy effect. [Sergio et al., 2025]

That is evidence for a possible return signal in an established cancer cell line. It does not show that ammonia initiates cancer, directly stabilizes MYC protein, or causes enough additional ammonia production to close the loop. Nor does it establish β-catenin as a necessary intermediate. The concentration dependence also argues against assuming that more ammonia always means more MYC.

Initiation and maintenance are different questions. A genetic change could activate MYC first, while a later metabolic consequence helps sustain the tumor. Alternatively, impaired clearance could precede elevated ammonia. Determining what keeps the system running may reveal an intervention even before its original starting point is known.

Connection	What the evidence supports	What remains open
MYC → ammonia	MYC-dependent glutamine metabolism can increase production.	Whether local production exceeds removal in a particular tumor.
Ammonia → MYC	A response observed in a limited experimental context.	Its generality and whether it completes a sustained feedback loop.
Ammonia → immune suppression	Functional impairment demonstrated in several experimental systems.	Which patients would benefit from an ammonia-directed intervention.

These are separate evidence streams. Combining their arrows produces a research hypothesis, not proof of the complete circuit.

Part IV / Where to intervene

Targeting the Environment MYC Helps Create

Direct MYC targeting remains an active research field: the investigational inhibitor OMO-103 reached a phase I trial that demonstrated target engagement. The ammonia perspective adds another possibility—intervening in a metabolic consequence of MYC activity. [Garralda et al., 2024]

Three approaches deserve comparison. The practical question is which one improves the balance between cancer survival and immune attack.

Research direction 01

Reduce Tumor Production

Test whether suppressing tumor MYC activity or its glutaminase-dependent metabolic output lowers local ammonia. MYC perturbation provides a biological rationale, but it cannot predict the result in every cancer. Measure ammonia alongside immune-cell function; a pathway change alone does not establish an immune benefit. [Wise et al., 2008]

Research direction 02

Increase Local Clearance

In colorectal cancer mouse models, ammonia clearance improved immune activity, and ornithine combined with anti-PD-L1 improved survival. This supports testing clearance as an immunotherapy partner. It does not establish that systemic ammonia-lowering drugs or supplements reproduce that effect in people. [Bell et al., 2023]

Research direction 03

Protect the Immune Cells

Memory CD8 T cells can use urea and citrulline cycle pathways to dispose of ammonia. This suggests an engineering question: could therapeutic immune cells be equipped to retain function in ammonia-rich tumors? Enhancing resilience would need to preserve killing capacity as well as survival. [Tang et al., 2023]

An unconventional extension

Convert a Local Waste Stream

Engineered bacteria have been designed to convert tumor ammonia into arginine, supporting antitumor immunity and combining with checkpoint blockade in mice. This offers a local metabolic intervention. Because arginine itself benefits T cells, the antitumor effect cannot be attributed solely to ammonia removal. [Canale et al., 2021]

Removing ammonia and blocking its reuse may have different consequences. Inhibiting a cancer cell’s ammonia-assimilation pathway could restrict its nitrogen supply while leaving more ammonia outside the cell. That is a mechanistic concern to test, rather than an assumed outcome. Tumor growth, local ammonia, and immune function should be measured together.

The most promising candidate setting would therefore be defined by measurements: substantial local ammonia exposure, an identifiable source or clearance defect, and immune dysfunction that improves when ammonia is reduced. MYC expression alone would be an incomplete way to select a tumor for this approach.

Part V / Making the hypothesis earn its arrows

What Would Demonstrate the Loop?

The decisive experiment must connect both directions in the same system. Comparing MYC levels and ammonia across unrelated tumors cannot establish which controls which.

1. Perturb MYC in the tumor cells. Measure ammonia production and local exposure early, before substantial cell loss could explain a decline. Track both production and assimilation.
2. Lower ammonia independently. Determine whether MYC protein and its transcriptional output fall before the tumor shrinks. Use approaches with different mechanisms to help separate ammonia effects from unrelated drug actions.
3. Test controlled add-back. Restore ammonia while controlling pH, nutrients, and other culture conditions. Ask whether MYC output and immune dysfunction return.
4. Show sustained coupling. Establish that ammonia-induced MYC activity increases ammonia production sufficiently to maintain the state. Repeat in additional tumor models and include immune-cell killing as a functional readout.

Two outcomes would be informative. If ammonia reduction lowers MYC and restores immune killing, it would support a coupled vulnerability. If MYC remains unchanged while killing improves, ammonia could still be a useful immune target. Its therapeutic relevance does not depend on proving that it came first.

The research opportunity is to identify tumors that depend on the ammonia-rich environment they inhabit—and determine whether changing that environment gives immune cells back the capacity to kill.

Selected Primary References

Publication years below follow the journal issue where applicable. Some articles appeared online the preceding year.

1. Wise DR et al. (2008). MYC regulation of glutaminolysis and glutamine dependence. PNAS.
2. Gao P et al. (2009). MYC, miR-23a/b, and mitochondrial glutaminase. Nature.
3. Bott AJ et al. (2015). MYC induction of glutamine synthetase through promoter demethylation. Cell Metabolism.
4. Spinelli JB et al. (2017). Ammonia recycling through glutamate dehydrogenase in breast cancer. Science.
5. Eng CH et al. (2010). Glutaminolysis-derived ammonia as a regulator of autophagy. Science Signaling.
6. Bell HN et al. (2023). Microenvironmental ammonia and T-cell exhaustion in colorectal cancer. Cell Metabolism.
7. Domagala J et al. (2025). Ammonia, mature perforin, and impaired NK- and T-cell antitumor activity. Cancer Research.
8. Gu J et al. (2026). Tumor-produced ammonia metabolism by regulatory T cells. Cell.
9. Sergio S et al. (2025). β-catenin/c-MYC and autophagy responses to different ammonia concentrations. Advanced Biology.
10. Garralda E et al. (2024). MYC targeting by OMO-103: a phase I solid-tumor trial. Nature Medicine.
11. Tang K et al. (2023). Ammonia detoxification and CD8 T-cell memory development. Nature Immunology.
12. Canale FP et al. (2021). Metabolic modulation of tumors with engineered bacteria. Nature.