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<p>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 <i>Foxa1</i> in <i>Pten</i>-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.</p>

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FOXA1 loss drives basal/squamous de-differentiation of prostate cancer and induces an immunosuppressive tumor microenvironment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月28日

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  • 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

摘要

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.