2026/03/28 by Lourdes Brea, Hongshun Shi, Viriya Keo +18 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #FOXO transcription factor regulation #Prostate Cancer Treatment and Research #Hippo pathway signaling and YAP/TAZ
paper · doi:10.1038/s41467-026-71121-8
openalex publication_date 2026/03/28 · openalex created_date 2026/03/29 · openalex updated_date 2026/08/01
FOXA1 is a prostate lineage-specifying transcription factor that is frequently dysregulated or mutated in prostate cancer (PCa). While FOXA1 has been reported to exhibit both PCa-promoting and -inhibitory functions, its role within an immune-proficient PCa context remains unclear. Here, we show that prostate-specific deletion of Foxa1 in Pten-deficient mice drives tumor progression by reprogramming luminal PCa cells toward a basal/squamous-like state and promoting an immunosuppressive tumor microenvironment. Histological and transcriptomic analyses reveal aggressive tumors with extensive basal/squamous features, a reactive stroma, and disorganized tissue architecture. Mechanistically, FOXA1 directly represses basal/squamous and inflammatory genes, which become activated upon its depletion. This is accompanied by an accumulation of immunosuppressive myeloid cells, dysfunctional T cells, and immunosuppressive cytokine signaling. Together, these findings demonstrate a tumor-suppressive role for FOXA1 as an enforcer of luminal identity, such that its loss drives basal/squamous de-differentiation, inflammatory response, and immunosuppression.