Researchers at MD Anderson have identified a tumor-suppressing protein that is shut down by excess glutamine in head and neck cancers, blunting the immune response. Blocking glutamine metabolism restored immune activity in preclinical models, pointing to a new way to help resistant tumors respond to treatment.
A protein that helps the immune system spot and attack cancer cells can be switched off by a common nutrient in the tumor’s surroundings, according to new research from The University of Texas MD Anderson Cancer Center.
In preclinical models of head and neck cancer, scientists found that high levels of glutamine, an amino acid that fuels cell growth, can silence a tumor-suppressing protein called BATF2. When BATF2 is shut down, the immune system’s ability to recognize and fight tumors is weakened.
The work, published in Nature Communications and led by Yu Leo Lei, an associate professor in the departments of Head and Neck Surgery, Cancer Biology and Translational Molecular Pathology, points to a potential new strategy: targeting glutamine metabolism to reawaken immune defenses in tumors that have been hard to treat.
Lei explained that researchers are beginning to look beyond the classic tumor suppressor genes that are damaged directly by mutations.
“The canonical tumor suppressors are frequently mutated or lost at the genetic level. Emerging evidence highlights the importance of a new type of tumor suppressor that is not frequently mutated but is epigenetically inhibited by unique metabolic cues in the tumor microenvironment,” he said in a news release.
BATF2 falls into this newer category. Rather than being commonly mutated, it can be epigenetically silenced, meaning its activity is turned off without altering the underlying DNA sequence. The trigger, this study shows, is the metabolic environment around the tumor, especially the abundance of glutamine.
BATF2 normally helps coordinate anti-tumor immune surveillance. It is highly expressed in epithelial cells, which line surfaces such as the mouth and throat, and in myeloid cells, a group of immune cells. The protein can directly activate the STING pathway, a key part of the body’s innate immune system that sparks production of Type I interferons. These signaling molecules help recruit and activate T cells, which can then attack cancer cells.
In patient tumor samples, the researchers found that higher BATF2 levels were strongly linked with stronger interferon and so-called Th1 immune signatures, both signs of an active, tumor-fighting immune response. In other words, when BATF2 is abundant, the immune system is more likely to be engaged against the cancer.
But many cancers, including head and neck tumors, are resistant to therapies that try to stimulate the STING pathway. Recent work in cancer biology has suggested that metabolism inside and around tumors can reshape gene activity through epigenetic changes, potentially explaining some of this resistance.
The MD Anderson team focused on glutamine, a nutrient that rapidly dividing cancer cells often consume in large amounts. They observed that BATF2 and interferon-related genes tended to be low when genes involved in glutamine metabolism were high, hinting at an inverse relationship.
In five preclinical models of head and neck cancer, the researchers tested what happens when tumors are exposed to a glutamine-rich environment. They found that excess glutamine led to epigenetic silencing of the BATF2 gene. As BATF2 levels dropped, interferon production fell, oxygen consumption by cancer cells increased and the tumors were better able to grow and evade immune detection.
The team then flipped the experiment. When they used drugs to block glutamine metabolism, interferon production was significantly restored. Cancer cells became more sensitive to drugs that target the STING pathway, and the overall antitumor immune response improved in these models.
The findings highlight a new way of thinking about tumor suppressors in the context of immunotherapy.
“This study characterizes a novel oral cancer tumor suppressor that drives immune surveillance but is inhibited by high levels of glutamine,” Lei added.
For patients with head and neck cancers, which can be difficult to treat and often recur, the study suggests a possible future approach: controlling glutamine levels or blocking its metabolism to boost BATF2 activity in the tumor microenvironment. That, in turn, could strengthen the immune response and help tumors that previously resisted STING-targeting treatments become more responsive.
The research is still at the preclinical stage, meaning it has been tested in laboratory and animal models, not yet in human clinical trials. More work will be needed to determine whether glutamine-blocking drugs are safe and effective in people with head and neck cancer, how best to combine them with existing therapies, and which patients are most likely to benefit.
Beyond one cancer type, the study adds to a growing body of evidence that the nutrients surrounding a tumor can shape how genes are turned on and off, and how the immune system behaves. As scientists continue to map these connections, they hope to design treatments that do more than attack cancer cells directly. The goal is to rewire the tumor environment itself so that the body’s own defenses can do their job more effectively.