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.
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Data availability
The whole-exome sequencing data are deposited in the NCBI SRA with a BioProject accession ID of PRJNA1147735. The BMDM bulk RNA-Seq data are deposited to the NCBI SRA with a BioProject accession ID of PRJNA1363923. The single-cell dataset is deposited to the NCBI SRA with BioProject accession numbers of PRJNA1111664 and PRJNA1298899. The processed bulk RNA-Seq data from human HNSCC specimens are publicly available through the NCBI Gene Expression Omnibus (GEO) with accession ID GSE310041. Raw individual-level sequencing data from human samples are not publicly available due to patient privacy concerns, but can be made available upon request after the establishment of a Data Use Agreement and/or a Material Transfer Agreement. The remaining data are available within the Article, Supplementary Information, or Source Data file. Source data are provided with this paper.
Code availability
The code for single-cell RNA-Seq analyses is made available through Github [https://github.com/yuyingxie/BATF2-IFN], which is linked to Zenodo (DOI: 10.5281/zenodo.17643493).
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Acknowledgements
The FLAG-STING expression plasmid is kindly provided by Dr. Glen N. Barber at the University of Miami. We sincerely thank Dr. Gabriel Nuñez at the University of Michigan for providing the Tcrd−/− mice. This project was funded by NIH grants R03DE027399 (Y.L.L.), R01 DE026728 (Y.L.L.), R01 DE030691 (J.J.M.), R01 DE031951 (J.J.M.), U01 DE033330 (Y.L.L.) and U01 DE029255 (Y.L.L.). Q.H. and L.W. were supported by U24 CA274159. The core facilities are supported, in part, by P30 CA016672.
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W.G., H.F.T., Y.W., Y.H., X.Z., Z.L., X.H., C.U., K.C.D., K.O., C.R.D., F.N., M.Z., W.C., Z.R.F., L.B., J.L. and Y.Y. performed experiments and contributed to data acquisition. W.G. and Y.L.L. designed the project with significant intellectual input from J.J.M., S.D., A.G.S. and D.N. Y.W., C.D.P., E.B. and Y.X. advised on statistical analysis and performed data analyses. Y.W., A.Y., Z.Z., Y.X. and Y.L.L. performed single-cell analyses and biostatistical analyses. Q.H. and L.W. performed analyses for the NOOC2 whole-exome sequencing and mutation profile data set. G.T.W. and S.B.C. provided completely de-identified discarded/archived human material. H.W. and S.A. provided key resources and technical support. M.Z. and J.N.M. provided key cell lines. W.G., H.F.T., Y.H., Y.X. and Y.L.L. wrote the manuscript, and all authors edited the manuscript and have read and agreed to its contents. Y.L.L. and J.J.M. supervised the study.
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Y.L.L. and J.J.M. are co-founders and serve on the advisory board of Saros Therapeutics Inc. Y.L.L. licensed NOOC1 cells to Kerafast Inc. and Applied Biological Materials Inc. The other authors do not have competing interests relevant to this study for disclosure.
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Gong, W., Taner, H.F., Wu, Y. et al. BATF2 is a glutamine-responsive tumour suppressor required for type-I interferon-dependent anti-tumour immunity. Nat Commun (2025). https://doi.org/10.1038/s41467-025-68027-2
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DOI: https://doi.org/10.1038/s41467-025-68027-2
