Cancer cell-specific FOXP3 licenses MMP19-dependent matrix remodeling and metastatic dissemination in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma and early metastatic dissemination, both of which contribute to its poor prognosis. While forkhead box protein 3 (FOXP3) is best known as a lineage-defining transcription factor in regulatory T cells (Tregs), its aberrant expression in cancer cell-specific FOXP3 (c-FOXP3) may also support tumor-cell-intrinsic progression. Our findings suggest that high c-FOXP3 expression is closely linked to aggressive disease behavior and metastatic progression in PDAC. c-FOXP3 enhanced migration, invasion within three-dimensional collagen-rich matrices, and dissemination in orthotopic models. Integrated transcriptomic analysis, chromatin immunoprecipitation, and wild-type versus binding-site-mutant promoter assays identified matrix metalloproteinase 19 (MMP19) as a direct transcriptional target of c-FOXP3. MMP19 silencing significantly attenuated c-FOXP3-driven migration, matrix invasion, and metastasis. Single-cell sequencing further showed that MMP19 is abundant in cancer-associated fibroblasts but also defines a distinct epithelial pool that is reduced after epithelial Foxp3 deletion. Pharmacological profiling did not identify a validated MMP19-selective inhibitor, whereas the FOXP3-targeting antisense oligonucleotide AZD8701 reduced FOXP3 together with MMP19 mRNA and was accompanied by lower PDAC-cell migration and invasion in vitro. Together, these findings extend the known functions of FOXP3 beyond its classical role in immune tolerance and define a tumor-cell-intrinsic c-FOXP3-MMP19 program that supports matrix-invasive behavior in PDAC and provide preliminary evidence that c-FOXP3 is pharmacologically accessible.