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

作者：Wang Gong, Hülya F. Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R. Donnelly, Felipe Nör, Chamila Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R. Fitzsimonds, Luke J. Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T. Wolf, Andrew G. Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B. Chinn, J MYERS, Shizuo Akira, Yuying Xie, James J. Moon, Yu L. Lei · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-68027-2 · 被引用次数：1 · 研究领域：interferon and immune responses、Cancer Immunotherapy and Biomarkers、Cancer, Hypoxia, and Metabolism

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...