Luminal Stem-like Cells in High-Risk/Locally Advanced Prostate Cancer Promote Resistance to Hormonal Therapy

<b>Introduction:</b> High-risk/locally advanced prostate cancer (HRLPC) accounts for a large proportion of prostate cancer cases in China and is associated with a high recurrence rate. Androgen deprivation therapy-based treatment offers limited benefits, which may be associated with changes in epithelial cells and the tumor microenvironment (TME) after treatment. However, the cellular composition and molecular characteristics of the subpopulations following hormonal treatment in HRLPC remain unclear. <b>Methods:</b> To investigate the molecular characteristics of residual tumor samples in HRLPC patients following hormonal therapy and to identify the reasons for their high recurrence rates, this study performed single-cell sequencing on nine HRLPC patients. Additionally, by establishing patient-derived organoids (PDOs) and conducting drug screening, we analyzed epithelial cell subpopulations at different treatment stages and explored potential therapeutic strategies. <b>Results:</b> This study identified a population of luminal stem-like epithelial cells (Lum stem-like) with high transcriptional activity of SOX9. After hormonal therapy, these cells were still alive and became the predominant component of epithelial luminal cells. Additionally, after hormonal therapy, the proportion of stromal components, such as fibroblasts and endothelial cells, significantly increased in the TME, and the intercellular communication between fibroblasts and other cells was enhanced. The level of immune infiltration decreased, but the proportion of FOXP3⁺ Treg cells increased, leading to an "exhausted" immune microenvironment state. We confirmed that PDOs can accurately reflect the epithelial subtypes of the primary tumor, such as Lum stem-like cells. Using 18 potential therapeutic agents at the organoid level for drug screening, the results showed that the Lum stem-like cells exhibited greater sensitivity to platinum-based drugs. <b>Conclusions:</b> This study identified the dominant Lum stem-like epithelial cell subpopulation, along with changes in the TME characterized by increased stroma and decreased immune infiltration after hormonal therapy in HRLPC. These findings can help guide the subsequent treatment strategies for HRLPC patients.