An oncogenotype-immunophenotype paradigm governing the myeloid landscape in genetically engineered mouse models of prostate cancer

2025 · doi:10.1101/2025.10.21.683668
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Abstract Distinct oncogenotypes sculpt divergent myeloid landscapes in prostate cancer. Using prostate-specific Ptenpc-/-, Ptenpc-/- Trp53pc-/-, Ptenpc-/- Smad4pc-/-, and Ptenpc-/- Trp53pc-/- Smad4pc-/- models, we identify a Smad4-loss-driven neutrophil-enriched subtype (NES) characterized by CXCL5, CXCL2, and CCL20 upregulation, polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration, and immune checkpoint resistance. In contrast, Smad4-intact tumors form macrophage-enriched subtypes (MES) responsive to immunotherapy. Mechanistically, Smad4 ablation activates YAP signaling and elevates histone epigenetic regulatory enzymes that enhance histone modification, chromatin accessibility, and transcription of neutrophil-recruiting cytokines. Genetic or pharmacologic inhibition of these enzymes suppresses chemokine expression, reduces neutrophil accumulation, restores CD8 T-cell activity, and limits tumor growth in immunocompetent hosts. Analyses of human prostate cancers support the findings from the murine NES prostate tumors. These findings establish a Smad4-YAP-epigenetic axis linking oncogenotype to immunophenotype and uncover a therapeutic vulnerability within the myeloid-dominant prostate tumor microenvironment. Competing Interest Statement The authors have declared no competing interest.

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