Targeting the CCL5/CCR5 axis in tumor-stromal crosstalk to overcome cisplatin resistance in neuroendocrine prostate cancer

  • J Exp Clin Cancer Res. 2025 Oct 28;44(1):296. doi: 10.1186/s13046-025-03552-y.
Bo Liu  #  1 ,  Weiwei Zhang  #  1 ,  Yiyi Ji  1 ,  Jiajin Wu  1 ,  Ruopeng Su  1 ,  Xinyu Liu  1 ,  Ang Li  1 ,  Kai Shen  1 ,  Xinyu Chai  1 ,  Haotian Wu  1 ,  Zehua Ma  1  2 ,  Cong Hu  1 ,  Zhou Jiang  3 ,  Liang Dong  1 ,  Yinjie Zhu  1 ,  Baijun Dong  1 ,  Wei Xue  4 ,  Jiahua Pan  5 ,  Qi Wang  6  7
Affiliations
  • 1. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China.
  • 2. Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550001, China.
  • 3. Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China.
  • 4. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China. [email protected].
  • 5. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China. [email protected].
  • 6. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China. [email protected].
  • 7. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200120, China. [email protected].
  • # Contributed equally.
PMID: 41152972 DOI: 10.1186/s13046-025-03552-y
Abstract

Background: Neuroendocrine Prostate Cancer (NEPC) is an aggressive subtype of Prostate Cancer with limited therapeutic options. Although cisplatin is recommended as a first-line treatment, its clinical efficacy is hindered by the rapid development of drug resistance, highlighting the urgent need for effective strategies to overcome cisplatin resistance.

Methods: We established a NEPC mouse allograft model and performed RNA Sequencing to identify genes associated with cisplatin resistance. The role of CCL5 in tumor-stromal crosstalk was investigated using immunofluorescence, ELISA assays, co-culture assays, and CCL5 knockout mice. Mechanistic studies were conducted to explore CCL5/CCR5-mediated signaling pathways. The therapeutic efficacy of cisplatin combined with maraviroc, an FDA-approved CCR5 Antagonist, was evaluated in vitro using NEPC cell lines and patient-derived organoids, and in vivo using NEPC mouse models.

Results: Here, we identify a tumor-stromal interaction mediated by the CCL5/CCR5 axis that drives cisplatin resistance in NEPC. Cisplatin-induced DNA damage promotes a cGAS-STING-dependent senescence program in cancer-associated fibroblasts (CAFs), resulting in the secretion of CCL5, a key senescence-associated secretory phenotype factor. CCL5 from CAFs binds to CCR5 on tumor cells, promoting the formation of a CCR5/β-arrestin1/p85 complex that activates the PI3K/Akt pathway. This activation enhances DNA repair, protecting tumor cells from cisplatin-induced Apoptosis. Pharmacologic inhibition of the CCL5/CCR5 pathway using maraviroc, an FDA-approved CCR5 Antagonist, sensitizes NEPC cells to cisplatin treatment and significantly prolongs survival in NEPC mouse models.

Conclusions: Our findings identify the CCL5/CCR5 axis as a key mediator of tumor-stromal crosstalk driving cisplatin resistance in NEPC. Mechanistically, CAF-derived CCL5 activates Akt signaling in tumor cells by promoting the formation of the CCR5/β-arrestin1/p85 complex. Targeting this pathway with maraviroc in combination with cisplatin offers a promising therapeutic strategy for overcoming drug resistance in NEPC.

Keywords
CCL5; Cancer-associated fibroblasts; Cisplatin resistance; Maraviroc; Neuroendocrine prostate cancer.
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