The prostate is an organ characterized by significant spatial heterogeneity. To better understand its intricate structure and cellular composition, we constructed a comprehensive single-cell atlas of the adult human prostate. Our high-resolution mapping effort identified 253,381 single cells and 34,876 nuclei sampled from 11 patients who underwent radical resection of bladder cancer, which were categorized into 126 unique subpopulations. This work revealed various new cell types in the human prostate and their specific spatial localization. Notably, we discovered four distinct acini, two of which were tightly associated with E-twenty-six transcription factor family (ETS)-fusion-negative prostate cancer. Through the integration of spatial, single-cell and bulk-seq analyses, we propose that two specific luminal cell types could serve as the common origins of prostate cancer. Additionally, our findings suggest that zone-specific fibroblasts may contribute to the observed heterogeneity among luminal cells. This atlas will serve as a valuable reference for studying prostate biology and diseases such as prostate cancer.

© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.