2. Academic Validation
  3. CX3CL1-CX3CR1 signaling orchestrates malignant progression of prostate cancer through luminal progenitor-macrophage crosstalk

CX3CL1-CX3CR1 signaling orchestrates malignant progression of prostate cancer through luminal progenitor-macrophage crosstalk

  • Cell Oncol (Dordr). 2026 Mar 23;49(2):59. doi: 10.1007/s13402-026-01179-5.
Yu Jiang # 1 2,  Yuchen Guo # 3,  Lizhuang Han 1 2,  Shiwei Wang 1 2,  Fang Wang 1 2,  Yongliang Zhao 4,  Jiajia Wang 1 2,  Junyan Han 1 2,  Miaomiao Liu 5,  Zhihua Liu 6,  Qin Zhang 7
Affiliations

Affiliations

  • 1 Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
  • 2 Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing, 100038, China.
  • 3 National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China.
  • 4 Suzhou Xi'an Jiaotong-Liverpool Technology Transfer Center, Suzhou, 215009, China.
  • 5 Laboratory Animal Resources Center, Tsinghua University, Beijing, 100084, China.
  • 6 Institute of Immunology, School of Basic Medicine, Tsinghua University, Medical Science Building, Haidian District, Beijing, 100084, China. [email protected].
  • 7 National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, No. 45, Changchun Street, Xicheng District, Beijing, 100053, China. [email protected].
  • # Contributed equally.
PMID: 41870750 DOI: 10.1007/s13402-026-01179-5
Abstract

Purpose: Progression to castration-resistant prostate Cancer (CRPC) is shaped by dynamic interactions within the tumor microenvironment (TME). However, the specific cellular crosstalk driving therapeutic resistance and metastasis remains incompletely defined. This study aims to identify key signaling axes between therapy-resistant luminal progenitor (luminal-2) cells and immune components in the TME, particularly tumor-associated macrophages (TAMs), and to determine how these interactions promote immunosuppression and Cancer stem-like cell expansion during disease progression.

Methods: We employed an integrative phenomics approach combining single-cell transcriptomics with genetically engineered mouse models (GEMMs) and orthotopic allograft models of prostate Cancer. Spatiotemporal changes in cell populations were profiled across disease stages. The functional contribution of the CX3CL1-CX3CR1 axis was evaluated through genetic ablation of CX3CR1 in host mice, followed by assessment of TAM infiltration, luminal progenitor cell dynamics, tumor growth, and immunosuppression signature score.

Results: Single-cell profiling revealed a distinct luminal-2 progenitor population with high CX3CL1 expression that recruits CX3CR1+ TAMs and supports a pro-tumoral program. These CX3CL1hi luminal-2 cells and CX3CR1hi TAMs expand in a stage-specific manner and co-evolve during CRPC progression, forming an immunosuppressive and pro-metastatic niche. Host CX3CR1 deletion disrupted this signaling axis, leading to reduced TAM infiltration, suppression of luminal progenitor cells expansion, and significant inhibition of tumor growth and progression.

Conclusion: The CX3CL1-CX3CR1 axis functions as a critical mediator of reciprocal signaling between luminal-2 progenitors and TAMs that promotes immune evasion, stemness maintenance, and therapeutic resistance in prostate Cancer. Disrupting this pathway impairs the pro-tumoral niche and may represent a promising therapeutic approach for advanced prostate Cancer.

Keywords

CX3CL1-CX3CR1 axis; Luminal progenitor cells (luminal 2 cells); Prostate cancer; Tumor-associated macrophages (TAMs).

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