A common amino acid found in everyday foods could play a surprisingly important role in helping the immune system recognize cancer and fight viral infections. Scientists at Rockefeller University have discovered that when the body lacks arginine, a key part of its immune defense system can stop working properly, potentially allowing dangerous cells and viruses to escape detection.
Arginine is an amino acid that the body produces naturally and also obtains from protein-rich foods. It is essential for making proteins that perform countless functions throughout the body. Researchers have long known that unusually low levels of arginine are associated with several diseases, including colon cancer, but exactly how this shortage affects the body’s defenses remains unclear.
Now, new research suggests that restoring arginine levels could help the immune system respond more effectively to serious threats. In experiments involving mice, increasing dietary arginine reduced the formation of colon cancer tumors and decreased the severity of influenza and SARS-CoV-2 infections. Remarkably, administering arginine after the mice had already contracted the flu also improved their outcomes.
The results, published in the journal Cellraise the possibility that an inexpensive, readily available supplement could eventually become a useful adjunct to cancer treatments and strategies to combat viral infections. However, additional research in humans is needed to determine whether the benefits observed in mice translate into effective treatments for humans.
How a missing nutrient could help cancer evade the immune system
The research was led by Sohail Tavazoie, who directs the Elizabeth and Vincent Meyer Laboratory of Cancer Systems Biology at Rockefeller University. His team has spent years studying how arginine influences the development and progression of cancer.
In 2023, researchers discovered that arginine deprivation in colon cancer cells caused them to accumulate more genetic mutations. These changes may contribute to the unpredictable behavior of cancer cells, raising important questions about how arginine shortages might influence disease.
The latest study reveals another potentially important consequence. When arginine becomes scarce, cells have trouble producing enough of an essential immune system protein called MHC-1. This protein acts as a warning system, helping immune cells identify potential dangers such as cancerous changes or viral infections.
Without enough MHC-1, abnormal or infected cells may become more difficult for the immune system to recognize.
Encouragingly, researchers also found that providing a moderate amount of arginine, comparable to the amount available in a few over-the-counter supplement tablets, could help restore production of this important protein.
“Our work reveals how a lack of arginine interferes with the immune system and suggests that increasing arginine consumption could prove beneficial,” says first author Qiushuang Wu, a postdoctoral fellow in the lab. “Perhaps this means it could be used in combination with other therapies to treat both cancer and viral infections.”
“Arginine supplementation could be easily tested in patients receiving immunotherapies or administered to high-risk populations exposed to viral pathogens,” suggests Tavazoie. “Since arginine is inexpensive and readily available, we hope that therapeutic and preventative studies can be undertaken soon.”
The surprising link between arginine and immune defenses
To understand why arginine has such a strong effect, researchers studied how cells use amino acids to make proteins.
Proteins are built from amino acids according to genetic instructions encoded in DNA. These instructions are copied into messenger RNA, which transmits the information to the cellular machinery responsible for producing proteins.
Instructions are read in groups of three genetic letters called codons. Each codon specifies an amino acid or provides another signal necessary for protein production. Arginine is unusual in that six different codons can specify it, reflecting the multiple ways its incorporation into proteins can be encoded.
Scientists already knew that changes in amino acid availability could affect cellular metabolism and signaling, two processes that help regulate how cells obtain energy and respond to their environment. What remained less clear was whether shortages of particular amino acids could directly influence the proteins produced by cells.
To investigate, Wu examined the effects of arginine availability on several disease models, including colon cancer, influenza, and SARS-CoV-2. Each of these diseases has previously been associated with abnormal levels of various amino acids.
The research was funded in part by the Stavros Niarchos Foundation (SNF) Global Infectious Disease Research Institute at Rockefeller University and the Weill Cancer East Hub.
“One of the most dramatic trends that emerged was that arginine was the most depleted amino acid in all of these diseases,” she says.
Why low levels of arginine can disrupt the immune system
In laboratory experiments using cultured cells, Wu examined how arginine shortages affected protein production. She identified 414 proteins whose levels abnormally decreased when arginine was scarce.
Many of these proteins were associated with biological functions already known to depend on arginine. However, the researchers discovered a more unexpected effect involving three genes of the HLA family.
These genes provide instructions for producing proteins associated with MHC-I (major histocompatibility complex class I), a critical component of the immune system’s ability to recognize threats.
MHC-I proteins are found on cell surfaces throughout the body. They act a bit like identification screens, presenting small fragments of proteins from inside the cell to immune cells called T cells.
When these displays reveal suspicious elements, such as proteins produced by a virus or abnormal proteins associated with cancer, T cells can recognize the danger and help coordinate an immune response.
But researchers found that arginine deficiency interfered with the production of these molecular warning signals.
The reason was ribosomes, tiny cellular machines that assemble proteins following genetic instructions. Because proteins involved in MHC-I production require arginine in many places, researchers suspected that insufficient supply might interfere with their assembly.
Further experiments confirmed these suspicions. When arginine was not available, the ribosomes stagnated as they tried to make MHC-I proteins. Without enough of the required amino acids, cells would not be able to carry out the process efficiently.
As a result, fewer MHC-I proteins reached the cell surface, reducing signals that would normally alert T cells to viral or cancer-associated proteins. This created an opportunity for dangerous cells to avoid immune detection.
“These findings are exciting because they reveal that consuming a specific amino acid can directly regulate gene expression in an organism by increasing the production of a protein enriched in that amino acid,” says Tavazoie. “We believe that such selective translational tuning of gene expression through dietary manipulations likely extends to many other proteins and amino acids.”
More arginine meant fewer colon cancer tumors in mice
After identifying the molecular mechanism, Wu studied whether changing the amount of arginine in an animal’s diet could influence the course of the disease.
The results were striking.
Mice fed a low-arginine diet developed more colon cancer tumors. In contrast, mice consuming greater amounts of the amino acid developed fewer tumors.
These results provided evidence that arginine availability can influence cancer development through its effects on the immune system, rather than simply altering the behavior of individual cancer cells.
The results also raised a broader question: If arginine helps immune cells recognize cancer, could it provide similar benefits when the body faces dangerous viruses?
Arginine also improved results against influenza and COVID-19 viruses
To explore this possibility, Wu collaborated with Heinz-Heinrich Hoffman, a research assistant professor in the Charles Rice Laboratory of Virology and Infectious Diseases.
Together, they examined the effects of dietary arginine on mouse models of influenza and SARS-CoV-2, the virus that causes COVID-19.
The results followed the same general pattern seen in the colon cancer experiments. Mice consuming more arginine showed less severe symptoms of viral infections, suggesting that adequate levels of the amino acid helped support the body’s immune defenses.
The researchers then made an even more surprising discovery.
Arginine does not appear to be beneficial only when consumed before an infection. Giving mice extra arginine after they had already been infected with the flu also improved their outcomes.
“Not only did mice on a high-arginine diet have milder symptoms of viral infections, but giving them arginine after a flu infection also improved their outcomes,” notes Wu. “This was very surprising. From our genetic models, we knew that manipulating arginine levels had a large effect on gene expression, but we didn’t expect that dietary manipulation would have the same impact.”
The observation suggests that changing nutrient availability could influence how the immune system responds even after a viral infection has taken hold.
Could a simple supplement improve treatments for cancer and viruses?
This finding has potentially important implications for understanding why some people become more vulnerable to cancer and serious viral infections.
Arginine levels naturally decline with age, and inadequate nutrition can further reduce the amount available to cells. Researchers suspect that these…
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