Arginine deficiency found to weaken the immunity against cancer and viruses

Rockefeller University researchers have found that a diet low in the amino acid arginine stalls production of a key immune protein, leaving cancerous and virus-infected cells better able to evade detection

The amino acid arginine helps to keep the human body functioning through the role it plays in the synthesis of proteins for a range of cellular processes. The body can produce arginine itself but it is also found in common high-protein foods. Low levels of arginine have been associated with a number of diseases, including colon cancer.

In 2023, Dr. Sohail Tavazoie, head of Rockefeller University’s ‘Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology’, New York, USA, and his team found that when colon cancer cells are starved of arginine, the number of mutations they accumulate increases.

Now, his team has discovered that a diet deficient in arginine also affects the immune system, as it stalls production of the major histocompatibility complex class I (MHC-1) protein which alerts the immune system to dangers such as a mutating cell or an invading virus.

Intriguingly, the team also found that a moderate dose of arginine – about as much as found in a couple of over-the-counter supplement tablets – could potentially rescue expression of the genes responsible for MHC-1 production.

“Our work reveals how a lack of arginine interferes with the immune system, and suggests that upping arginine intake could prove beneficial,” said Dr. Qiushuang Wu, the paper’s first author and a postdoctoral researcher in the Tavazoie laboratory.

“Perhaps that means it could be used in combination with other therapies to treat both cancer and viral infections,” she said.

“Arginine supplementation could be readily tested in patients receiving immunotherapies or given to high-risk populations exposed to viral pathogens.

“Considering that arginine is inexpensive and readily available, we hope that therapeutic and preventative studies could be undertaken soon,” Wu added.

Amino acids are known as the building blocks of proteins but they too have building blocks of their own which are known as codons. Codons are triplets of DNA bases, each of which carries the instructions used to produce a single amino acid. Arginine’s importance is underscored by the fact that six different codons carry the instructions to produce it.

It is already well established that fluctuations in amino acid levels can influence cellular metabolism and signalling, although whether such changes can alter gene expression has remained poorly understood.

In the current study Wu explored whether changes in arginine levels caused by diet or disease can alter gene expression across a variety of disease models, including colon cancer, influenza and severe acute respiratory syndrome coronavirus 2 – the virus responsible for the COVID-19 pandemic – all of which have been documented to involve abnormal levels of various amino acids.

“One of the most dramatic patterns to emerge was that arginine was the most depleted amino acid in all of these diseases,” Wu said.

In cell cultures, Wu tracked which genes were affected by lower levels of arginine. She identified 414 proteins present in abnormally low numbers, most of which were coded by genes linked to arginine’s known molecular roles. More surprisingly, a lack of arginine was found to hamper the expression of a trio of human leukocyte antigen genes that code for MHC-1 proteins. Found on cell surfaces across the body, MHC-1 presents foreign proteins to T cells which in turn signal other immune cells to mount a defence.

Because the MHC-1 protein is composed of many arginine codons, it made sense that a lack of arginine would be detrimental to production of the protein in some way, although exactly where the problem lay remained unclear. Through further experiments, Wu found that, in an arginine-starved environment, ribosomes – the molecular machines that manufacture proteins – stalled and were unable to translate MHC-1, because they lacked the arginine required to do so. This meant that far fewer of the proteins needed to alert T cells to the presence of cancer or viral proteins were produced which allowed the affected cells to evade detection.

“These findings are exciting because they reveal that consumption of a specific amino acid can directly regulate gene expression in an organism by increasing production of a protein enriched in that amino acid,” Tavazoie said.

“We believe that such selective translational tuning of gene expression through dietary manipulation likely extends to many other proteins and amino acids,” he added.

In mouse models, Wu tested the effect of different levels of dietary arginine. Mice that received a low-arginine diet developed more colon tumours while those that received a higher amount developed fewer.

In collaboration with a research assistant professor in Charles Rice’s Laboratory of Virology and Infectious Disease at Rockefeller – Dr. Heinz-Heinrich Hoffman – Wu then repeated these dietary experiments using influenza and SARS-CoV-2 mouse models. The pattern held but also revealed an unexpected twist.

“Not only did mice with an arginine-rich diet have milder symptoms from viral infections, giving the mice arginine after influenza infection improved their outcomes too,” Wu said.

“That was very surprising. From our genetic models, we knew manipulating arginine levels had a strong effect on gene expression but we didn’t expect the dietary manipulation to be equally impactful,” she added.

“Qiushuang’s findings illuminate how poor diet and ageing – during which arginine levels naturally decline – could create the perfect storm for the initiation of colon cancer. Similarly, age-related arginine loss could partially contribute to the greater mortality caused by respiratory viruses,” Tavazoie said.

“We’re also investigating whether making dietary changes to other amino acids has beneficial effects in a variety of disease contexts. There [is] no doubt more discoveries [are] to come,” he said.

Together, the findings describe a novel, diet-based mechanism by which arginine levels can directly influence the immune system’s ability to detect cancerous and virally infected cells – one that the study’s authors suggest could inform low-cost strategies to complement existing cancer treatments and antiviral therapies.

For further reading please visit: 10.1016/j.cell.2026.07.020