Abstract
The cGAS-STING pathway plays a central role in controlling tumor progression through nucleic acid sensing and type I Interferon production. Here, we identify Poly(rC) Binding Protein 1 as a tumor suppressor that amplifies cGAS-STING signaling in breast cancer. Using patient datasets and a transgenic mouse model with conditional PCBP1 knockout in mammary epithelial cells, we show that PCBP1 expression correlates with improved survival, reduced tumor burden, increased type I Interferon and Interferon Stimulated Gene expression, and elevated cytotoxic T cell infiltration. Mechanistically, PCBP1 binds cytosine-rich single-stranded motifs via its KH domains and increases cGAS affinity to these nucleic acids. Mutation of PCBP1’s conserved GXXG loops impairs nucleic acid binding and cGAS activation. Although cGAS is a double-stranded DNA sensor with no intrinsic sequence specificity, we uncover that the single-stranded nucleic-acid binding protein PCBP1 enhances cGAS sensing by engaging sequence-specific motifs, acting as a nucleic acid co-sensor that impairs tumorigenesis.
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Data availability
Bulk and single nuclei RNA-sequencing datasets generated during this study are deposited in the Gene Expression Omnibus (GEO) under accession numbers GSE307616 and GSE307750, respectively. Source data are provided with this paper in the supplementary data. The TCGA BRCA dataset is available online at https://www.cancer.gov/tcga. The Tabula Muris dataset is available online at http://tabula-muris.sf.czbiohub.org. Unedited Western blot images are available in the Supplementary Information.
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Acknowledgements
We would like to thank all members of Dr. Philip Howe’s laboratory, Dr. Shikhar Mehrotra, and Paramita Chakraborty for their technical help and helpful feedback. We also thank members of the Hollings Cancer Centre Translational Science Shared Resource, the Bioinformatics Core and the Flow Cytometry & Cell Sorting Shared Resource. This work was supported by the National Institutes of Health, National Cancer Institute grant [CA154663] to P.H.H. The work was also supported in part by the Translational Science Shared Resource, Bioinformatics Core and Flow Cytometry & Cell Sorting Shared Resource, Hollings Cancer Centre, Medical University of South Carolina [P30 CA138313]. Funding for open access charge: National Institutes of Health.
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C.F. conceived the study, designed the methodology, acquired all data, and wrote the manuscript. J.A.Q.K. assisted with EMSAs, and B.M. contributed additional methodological support. P.C. provided expertise in methodology and acquisition of flow cytometry data, with resource support from S.M. Library preparation for bulk and single-nuclei RNA sequencing was performed by S.V. and Romeo Martin. Bioinformatic analysis of bulk RNA sequencing was carried out by C.F., and single-nuclei RNA sequencing analysis by B.G. A.D. analysed the CD8/CD3 multiplex IHC. Additional supervision was provided by B.V.H. and P.H.H.
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Fréreux, C., Karam, J.A.Q., Howley, B.V. et al. PCBP1 binding to single-stranded poly-cytosine motifs enhances cGAS sensing and impairs breast cancer development. Commun Biol (2026). https://doi.org/10.1038/s42003-025-09456-z
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DOI: https://doi.org/10.1038/s42003-025-09456-z
