BATF2 is a glutamine-responsive tumor suppressor essential for type I interferon-dependent anti-tumor immunity 2283

作者：Yu L. Lei, Wang Gong, Hülya F. Taner, Yuesong Wu, Zaiye Li, Wanqing Cheng, Qiang Hu, Christopher R. Donnelly, Felipe Nör, HE Yu-min, Zhiqian Zhai, Zackary R. Fitzsimonds, Luke J. Broses, Jiaqian Li, Emily Bellile, Kohei Okuyama, Shadmehr Demehri, Deepak Nagrath, Gregory T. Wolf, Yanbao Yu, Haitao Wen, Lei Wei, Andrew G. Sikora, Steven B. Chinn, Shizuo Akira, Yuying Xie, James J. Moon · 发表于：The Journal of Immunology · 年份：2025 · DOI：10.1093/jimmun/vkaf283.218 · 研究领域：interferon and immune responses、Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers

Abstract Description Recent evidence highlights the significance of a new type of tumor suppressors which are not frequently mutated but inhibited by metabolic cues in initiating cancers. Here we identify BATF2 as a novel tumor suppressor gene whose expression is epigenetically silenced by glutamine in the tumor microenvironment (TME). We utilized three cohorts of human squamous cell carcinomas to find that BATF2 correlates with type-I interferon (IFN-I) signatures, with even stronger correlation coefficients than a positive control, STING. As a molecular mechanism, we found that the phosphorylation of BATF2 at S227 promotes the phosphorylation and oligomerization of STING. BATF2 deficiency or high glutamine levels result in a metabolic profile unfavorable for IFN-I production. An isocaloric glutamine-rich diet dampens STING agonist-mediated tumor control, abolishing STING-mediated effector cell expansion in the TME. Cancer-specific BATF2 expression promotes an Id2-centered T-cell signature, reduces T-cell exhaustion, and triggers potent tumor rejection in an IFN-I and T-cell-dependent fashion. Utilizing syngeneic, orthotopic, and cigarette smoke carcinogen-induced squamous cell carcinoma models, we found that host deficiency of Batf2 results in increased infiltration of CD206+ myeloid cells and reduced CD8+ T-cells, accelerating cancer initiation. Overall, we reveal a new type of tumor suppressor BATF2 whose loss is mediated by metabolic cues in the TME and drives cancer imm...