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  3. Single-cell sequencing unveils the transcriptomic landscape of castration-resistant prostate cancer-associated fibroblasts and their association with prognosis and immunotherapy response

Single-cell sequencing unveils the transcriptomic landscape of castration-resistant prostate cancer-associated fibroblasts and their association with prognosis and immunotherapy response

  • BMC Cancer. 2025 Apr 30;25(1):813. doi: 10.1186/s12885-025-14212-x.
Yifeng Qiu 1 2 3 4,  Yuhan Wang 1 2 3,  Jiahe Liu 1 2 3,  Kai Sun 5 6,  Baohua Liu 7,  Qi Hou 8 9 10
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China.
  • 2 Department of Urology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China.
  • 3 Shenzhen Key Laboratory for Systemic Aging and Intervention (SAI), Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, School of Basic Medical Sciences, Marshall Laboratory of Biomedical Engineering, National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, Shenzhen University, Shenzhen, Guangdong, China.
  • 4 International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen, China.
  • 5 Department of Radiology, the Third People's Hospital of Longgang District, Shenzhen, China.
  • 6 Shenzhen Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, 518116, China.
  • 7 Shenzhen Key Laboratory for Systemic Aging and Intervention (SAI), Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, School of Basic Medical Sciences, Marshall Laboratory of Biomedical Engineering, National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, Shenzhen University, Shenzhen, Guangdong, China. ppliew@szu.edu.cn.
  • 8 Department of Urology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China. qi_hou@foxmail.com.
  • 9 Shenzhen Key Laboratory for Systemic Aging and Intervention (SAI), Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, School of Basic Medical Sciences, Marshall Laboratory of Biomedical Engineering, National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, Shenzhen University, Shenzhen, Guangdong, China. qi_hou@foxmail.com.
  • 10 International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen, China. qi_hou@foxmail.com.
PMID: 40307786 DOI: 10.1186/s12885-025-14212-x
Abstract

Background: The tumor microenvironment (TME) is increasingly acknowledged as a determinant in the malignant transformation and progression of castration-resistant prostate Cancer (CRPC). Cancer-associated fibroblasts (CAFs), as a pivotal stromal cellular component in TME, are implicated in tumor progression and immune escape. However, the molecular characteristics and biological functions of CRPC-CAFs in prostate Cancer necessitate further investigation.

Methods: We ascertained the differential transcriptomic profiles between CRPC-CAFs and PCa-CAFs through single-cell RNA-sequencing (scRNA-seq). Bulk RNA-seq data were employed to assess the prognostic implications of CRPC-CAFs in PCa. In addition, we examined the impact of CRPC-CAFs on the efficacy of immunotherapy and the composition of the tumor immune milieu. Furthermore, a subcutaneous PCa model was applied to determine the potential of TGF-β signaling blockade to augment the response to immunotherapeutic interventions.

Results: We observed a pronounced increase in the proportion of CAFs in CRPC compared to those in primary PCa. The functional pathways implicated in TGF-β signaling and ECM remodeling were remarkably upregulated in CRPC-CAFs. Moreover, gene regulatory network analysis uncovered substantial differences in the transcription factor activity profiles between CRPC-CAFs and PCa-CAFs. The elevated CRPC-CAFs abundance was associated with diminished recurrence-free survival and immunotherapy insensitivity. Substantially elevated infiltration of inhibitory immune cells and upregulated expression levels of immunosuppressive molecules were observed in patients with high CRPC-CAFs abundance. Importantly, administration of anti-TGF-β therapy remarkably potentiated the efficacy of anti-PD-1 immunotherapy through upregulating the anti-tumor immune response in the PCa model.

Conclusion: Our results highlighted the impact of CRPC-CAFs on clinical prognosis and immunosuppressive tumor milieu, indicating that CRPC-CAFs may function as a promising therapeutic target for CRPC.

Keywords

Cancer-associated fibroblasts; Castration-resistant prostate cancer; Clinical outcomes; Immune infiltration; Single-cell RNA-sequencing.

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