This study integrates single-cell RNA sequencing, spatial transcriptomics, and bulk ATAC-seq to analyze the cellular heterogeneity and interactions in the prostate cancer (PCa) microenvironment. Key findings include the identification of a stemness subset of club cells marked by SOX9high and ARlow expression, which is enriched after neoadjuvant androgen-deprivation therapy (ADT). The study also reveals a reduction in CD8+ CXCR6+ T cells, which function as effector T cells, in patients with malignant PCa. Spatial transcriptomic analysis using machine learning and computational intelligence identifies cellular diversity and cell-cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are examined, and the immunosuppressive microenvironment in advanced PCa is associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. The study provides a comprehensive understanding of the stage-specific PCa microenvironment at single-cell resolution, highlighting the reciprocal crosstalk between tumor and stromal cells, which can aid in PCa diagnosis and therapy.This study integrates single-cell RNA sequencing, spatial transcriptomics, and bulk ATAC-seq to analyze the cellular heterogeneity and interactions in the prostate cancer (PCa) microenvironment. Key findings include the identification of a stemness subset of club cells marked by SOX9high and ARlow expression, which is enriched after neoadjuvant androgen-deprivation therapy (ADT). The study also reveals a reduction in CD8+ CXCR6+ T cells, which function as effector T cells, in patients with malignant PCa. Spatial transcriptomic analysis using machine learning and computational intelligence identifies cellular diversity and cell-cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are examined, and the immunosuppressive microenvironment in advanced PCa is associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. The study provides a comprehensive understanding of the stage-specific PCa microenvironment at single-cell resolution, highlighting the reciprocal crosstalk between tumor and stromal cells, which can aid in PCa diagnosis and therapy.