PCBP1 binding to single-stranded poly-cytosine motifs enhances cGAS sensing and impairs breast cancer development

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.