High BATF2 expression potentiated anti-tumor immunity and was associated with better clinical outcomes. a, The relative percentage of each cluster for TILs between HPV and HPV+ HNSCC (n = 26) is shown. The significantly changed clusters are labeled in red. b, The distribution profile of BATF2 expression across the 25 clusters from human HNSCC (n = 26) TILs is shown. Credit: Nature Communications (2025). DOI: 10.1038/s41467-025-68027-2

A novel tumor suppressor, BATF2, can be silenced by factors in the tumor microenvironment, leading to a reduced immune response in five preclinical models of head and neck cancer, according to researchers from The University of Texas MD Anderson Cancer Center.

The study, published in Nature Communications, was led by Yu Leo Lei, D.D.S., Ph.D., associate professor of Head and Neck Surgery, Cancer Biology and Translational Molecular Pathology. The results demonstrate that glutamine in the tumor microenvironment can cause epigenetic silencing of BATF2, which affects the STING signaling pathway and overall immune response.

"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," Lei said. "This study characterizes a novel oral cancer tumor suppressor that drives immune surveillance but is inhibited by high levels of glutamine."

BATF2 and how it helps with immunity

BATF2 is a tumor suppressor involved in regulating immune responses, helping to maintain anti-tumor immune surveillance. BATF2 is highly expressed by epithelial cells and myeloid cells, and it can directly activate the STING pathway—which plays a key role in innate immunity by triggering Type-I interferon (IFN-I) production to drive T cell-mediated protection against tumors.

In this study, researchers found that BATF2 levels correlate strongly with IFN-I and Th1 immune signatures in patient tumors, meaning that high levels of BATF2 help recruit immune cells to attack tumors.

How glutamine affects BATF2 and cancer cells

Many cancers are resistant to treatments that trigger the STING pathway. More recently, studies have shown that epigenetic changes—which turn genes on and off without changing the actual DNA sequence—can occur from metabolic cues in the tumor microenvironment.

In particular, BATF2 and IFN-I genes are inversely correlated with genes involved in the metabolism of glutamine—an amino acid that cells use for growth—suggesting a possible connection.

The study showed that a glutamine-rich diet silences the BATF2 gene, leading to a weakened immune response, lower levels of IFN-I production and higher oxygen consumption, allowing cancer cells to grow and avoid immune detection. Using drugs that inhibit glutamine metabolism significantly restored IFN-I production and sensitized cancer cells to drugs that target the STING pathway, improving the overall antitumor response.

What this means for patients with head and neck cancer

While these results are preclinical and further studies are needed, these findings suggest that controlling glutamine levels to enhance BATF2 expression in the tumor microenvironment could potentially improve the immune response in patients with head and neck cancers that were resistant to treatments that affect the STING pathway.

More information

Wang Gong et al, BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity, Nature Communications (2025). DOI: 10.1038/s41467-025-68027-2

Journal information: Nature Communications

Citation: High glutamine levels suppress immune response in head and neck cancer tumors (2026, January 7) retrieved 7 January 2026 from https://medicalxpress.com/news/2026-01-high-glutamine-suppress-immune-response.html

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