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  3. Pericytes in castration-resistant prostate cancer associated with disease progression and immunotherapy response: insights from single-cell analysis

Pericytes in castration-resistant prostate cancer associated with disease progression and immunotherapy response: insights from single-cell analysis

  • Cancer Cell Int. 2025 Jun 3;25(1):200. doi: 10.1186/s12935-025-03838-3.
Yifeng Qiu 1 2 3 4,  Yuhan Wang 1 2 3,  Jiahe Liu 1 2 3,  Kai Sun 5 6,  Shigeo Horie 7,  Zhitong Bing 8 9,  Qi Hou 10 11 12
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, 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 Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
  • 8 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China. bingzt@impcas.ac.cn.
  • 9 Energy Science and Technology Guangdong Laboratory, Huizhou, Guangdong, China. bingzt@impcas.ac.cn.
  • 10 Department of Urology, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, China. qi_hou@foxmail.com.
  • 11 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.
  • 12 International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen, China. qi_hou@foxmail.com.
PMID: 40462105 DOI: 10.1186/s12935-025-03838-3
Abstract

Background: The current immunotherapeutic strategies yield limited therapeutic benefits in patients with castration-resistant prostate Cancer (CRPC) due to its immunologically "cold" tumor milieu. Pericytes play a pivotal role in facilitating metastatic dissemination and modulating immune response in malignancies. Our investigation is designed to decipher the biological effects of pericytes on CRPC and their interactions with the tumor microenvironment.

Methods: We leveraged single-cell transcriptomics and immunofluorescence staining to ascertain the presence and spatial distribution of pericytes in prostate Cancer (PCa). Subsequently, we thoroughly delineated the phenotypic and functional characteristics of the CRPC-pericytes subpopulation. The clinical and prognostic significance of CRPC-pericytes was assessed by employing several bulk RNA-seq and microarray datasets. Additionally, we examined the association between the abundance of CRPC-pericytes and immunological features in the PCa microenvironment. Furthermore, the RM-1 subcutaneous tumor model was leveraged to assess the synergistic efficacy of platelet-derived growth factor (PDGF) signaling inhibition in conjunction with immunotherapeutic interventions.

Results: We discerned pericytes according to their marker genes and observed the α-SMA-positive pericytes encircling the vasculature in PCa and adjacent normal tissues. In the CRPC-pericytes subpopulation, a pronounced upregulation of PDGF signaling and angiogenesis was observed, whereas antitumor immunity-related pathways were suppressed. In addition, CRPC-pericytes displayed notably enhanced interactions with endothelial cells, fibroblasts, and myeloid cells, compared to PCa-pericytes. Patients with elevated prevalence of CRPC-pericytes exhibited notably reduced recurrence-free survival and unresponsiveness to immunotherapeutic interventions. Moreover, CRPC-pericytes were positively associated with immunosuppressive properties of the TME. Notably, combinatorial application of PDGFR Inhibitor and anti-PD-1 therapy elicited substantial synergistic antitumor effects in murine PCa models.

Conclusion: Our investigation uncovers a CRPC-pericytes subpopulation implicated in Cancer progression and immunosuppression, suggesting that therapies targeting the phenotypic transition of pericytes could act synergistically with immunotherapeutic regimens to improve survival rates in CRPC.

Keywords

Castration-resistant prostate cancer; Immune microenvironment; PDGF signaling; Pericytes; Single-cell transcriptomics.

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