Faculty, Staff and Student Publications

Publication Date

12-29-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-68027-2

PMID

41457098

PMCID

PMC12868817

PubMedCentral® Posted Date

12-29-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206+ myeloid cells and reduced effector CD8+ T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape.

Keywords

Humans, Glutamine, Animals, Head and Neck Neoplasms, Basic-Leucine Zipper Transcription Factors, Squamous Cell Carcinoma of Head and Neck, Tumor Suppressor Proteins, Interferon Type I, Mice, Mice, Inbred C57BL, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Mice, Knockout, Male, Membrane Proteins, Oral cancer, Tumour immunology, Innate immunity, Cancer metabolism

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.