FOXA1 loss drives basal/squamous de-differentiation of prostate cancer and induces an immunosuppressive tumor microenvironment
- Lourdes Brea
- Hongshun Shi
- Viriya Keo
- Jing Huang
- Liu Peng
- Qi Chu
- Wanqing Xie
- Yinghua Xie
- Sambhavi Senthil
- Matthew T. Breneman
- Jie Fan
- Ping Xie
- Xiaodong Lu
- David J. DeGraff
- Sarki A. Abdulkadir
- Ximing Yang
- David Kosoff
- Jonathan C. Zhao
- Bin Zhang
- Jian Hu
- Jindan Yu
2026-03-28
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.