Abstract

Although recent studies have shown that 2′3′-cyclic GMP-AMP synthase (cGAS) has both canonical cytoplasmic and non-canonical nuclear functions, the role of nuclear cGAS in cancer metastasis remains unclear. Here, we identify a STING-independent mechanism by which nuclear cGAS activates Wnt/β-catenin signaling to promote metastasis in triple-negative breast cancer (TNBC). Protein kinase C alpha (PKCα) phosphorylates cGAS at Ser120, facilitating its nuclear translocation. Once in the nucleus, cGAS disrupts the interaction between β-catenin and tripartite motif-containing protein 33 (TRIM33), preventing β-catenin ubiquitination and promoting its stabilization, thereby activating Wnt/β-catenin signaling. PKCα thus acts as a key regulator of this non-canonical, cGAS-driven metastatic pathway. Therapeutic transactivator of transcription (TAT) peptides inhibiting cGAS phosphorylation significantly reduce metastasis. Clinically, elevated nuclear cGAS expression is associated with increased metastasis in TNBC cohorts. Together, these findings delineate a PKCα-cGAS-TRIM33 axis that regulates nuclear β-catenin stability and establish cGAS phosphorylation as a promising theragnostic target for TNBC metastasis.