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Cancer-Associated Fibroblasts in Prostate Cancer: Unraveling Mechanisms and Therapeutic Implications

Yang Wu1,#,*, Dong Xu1,#, Run Shi1, Mingwei Zhan2, Shaohui Xu3, Xin Wang4, Jianpeng Zhang5, Zhaokai Zhou6, Weizhuo Wang7, Yongjie Wang8, Minglun Li9, Zihao Xu10,*, Kaifeng Su11,*
1 The First Clinical School, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, China
2 Department of Urology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, 310007, China
3 Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, China
4 Department of Oncology, Jiangsu Cancer Hospital, Nanjing, 210009, China
5 Department of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510030, China
6 Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
7 Center for Reproductive Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, 215000, China
8 Proteomics and Cancer Cell Signaling Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
9 Department of Radiation Oncology, Lueneburg Municipal Hospital, Lueneburg, 21339, Germany
10 Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
11 The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250013, China
* Corresponding Author: Yang Wu. Email: email; Zihao Xu. Email: email; Kaifeng Su. Email: email
# These authors contributed equally to this work

Oncology Research https://doi.org/10.32604/or.2025.073265

Received 14 September 2025; Accepted 14 November 2025; Published online 23 December 2025

Abstract

Prostate cancer (PCa) remains a major cause of cancer-related mortality in men, largely due to therapy resistance and metastatic progression. Increasing evidence highlights the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), as a critical determinant of disease behavior. CAFs constitute a heterogeneous population originating from fibroblasts, mesenchymal stem cells, endothelial cells, epithelial cells undergoing epithelial–mesenchymal transition (EMT), and adipose tissue. Through dynamic crosstalk with tumor, immune, endothelial, and adipocyte compartments, CAFs orchestrate oncogenic processes including tumor proliferation, invasion, immune evasion, extracellular matrix remodeling, angiogenesis, and metabolic reprogramming. This review comprehensively summarizes the cellular origins, phenotypic and functional heterogeneity, and spatial distribution of CAFs within the prostate TME. We further elucidate the molecular mechanisms by which CAFs regulate PCa progression and therapeutic resistance, and critically evaluate emerging strategies to therapeutically target CAF-mediated signaling, metabolic, and immune pathways. By integrating recent advances from single-cell and spatial transcriptomics (ST), our objective is to provide a holistic framework for understanding CAF biology and to highlight potential avenues for stromal reprogramming as an adjunct to current PCa therapies.

Keywords

Prostate cancer; cancer-associated fibroblasts; tumor microenvironment; therapy resistance
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