Journal Article

BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity

Broses, Luke, Li, Jiaqian, He, Yumin, Wolf, Gregory T., Chinn, Steven B., Yu, Yanbao, Zhou, Xingwu, Debnath, Kala Chand, Cheng, Wanqing, Myers, Jeffrey N., Okuyama, Kohei, Sikora, Andrew G., Demehri, Shadmehr, Perera, Chamila D., Ursin, Charisse, Wen, Haitao, Hu, Qiang, Hu, Xin, Taner, Hülya F., Moon, James J., Wu, Yuesong, Yunesi, Arash, Nör, Felipe, Wei, Lei, Li, Zaiye, Zhai, Zhiqian, Donnelly, Christopher R., Zhao, Mei, Xie, Yuying, Fitzsimonds, Zackary R., Bellile, Emily, Gong, Wang, Nagrath, Deepak, Lei, Yu Leo, Akira, Shizuo

2025

Overview

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. STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/31 / 13/51 / 14/19 / 14/63 / 38/109 / 38/23 / 38/39 / 38/77 / 38/88 / 49/15 / 49/91 / 631/250/262 / 631/67/1536/1665 / 631/67/2327 / 631/67/580 / 82/1 / 82/80 / Animals / Basic-Leucine Zipper Transcription Factors - genetics / Basic-Leucine Zipper Transcription Factors - immunology / Basic-Leucine Zipper Transcription Factors - metabolism / Cancer / Carcinogens / CD8 antigen / Cell Line, Tumor / Cells / Cigarette smoke / Correlation analysis / Correlation coefficient / Correlation coefficients / Datasets / Effector cells / Female / Gene Expression Regulation, Neoplastic / Glutamine / Glutamine - metabolism / Head & neck cancer / Head and neck carcinoma / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - immunology / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - pathology / Human papillomavirus / Humanities and Social Sciences / Humans / Immunity (Disease) / Immunogenicity / Interferon / Interferon Type I - immunology / Interferon Type I - metabolism / Kinases / Lymphocytes T / Male / Membrane Proteins - metabolism / Metastases / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Myeloid cells / Oligomerization / Oxygen consumption / Phosphorylation / Science / Science (multidisciplinary) / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - genetics / Squamous Cell Carcinoma of Head and Neck - immunology / Squamous Cell Carcinoma of Head and Neck - metabolism / Squamous Cell Carcinoma of Head and Neck - pathology / Suppressors / Tumor microenvironment / Tumor suppressor genes / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - immunology / Tumor Suppressor Proteins - metabolism / Tumors