Prostate cancer stands as the second most common malignancy among men, notorious for its intricate heterogeneity, especially evident in metastatic disease. This complexity presents substantial challenges in treatment efficacy and patient prognosis.This study endeavors to elucidate the multifaceted roles of cancer-associated fibroblasts within the tumor microenvironment of prostate cancer, with a focus on their implications for disease prognosis and the potential for novel immunotherapeutic strategies.Leveraging advanced single-cell RNA sequencing technology, we meticulously characterized the diverse CAF subpopulations within prostate cancer samples. Our analysis identified four predominant subsets: C0 IER2+, C1 ABCA8+, C2 ABI3BP+, and C3 MEOX2+. We conducted comprehensive gene expression profiling to construct a robust prognostic model reflecting the clinical relevance of these subpopulations.C1 ABCA8+ fibroblasts demonstrated heightened proliferative activity, underscoring their pivotal role in fostering tumor growth and metastasis via intricate signaling pathways. In vitro experiments verified that the T transcription factor NFAT5 of C1 ABCA8+ fibroblasts subpopulation was knocked down in LNCaP clone FGC and 22Rv1 cell lines, which was closely related to the proliferation of PC. Moreover, we identified key genes linked to patient outcomes and immune landscape alterations, reinforcing the prognostic significance of CAF characteristics in this context.This investigation illuminates the critical potential of targeting CAFs to augment immunotherapeutic approaches in prostate cancer. Our findings contribute to a deeper understanding of the TME's complexity, advocating for further exploration into CAF-targeted therapies aimed at enhancing treatment responses and ultimately improving patient outcomes.Copyright © 2024. Published by Elsevier Inc.