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

作者：Bo Liu, Weiwei Zhang, Yiyi Ji, Jiajin Wu, Ruopeng Su, Xinyu Liu, Ang Li, Kai Shen, Xinyu Chai, Haotian Wu, Zehua Ma, Cong Hu, Zhou Jiang, Liang Dong, Yinjie Zhu, Baijun Dong, Wei Xue, Jiahua Pan, Qi Wang · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03552-y · 被引用次数：12 · 研究领域：Chemokine receptors and signaling、Telomeres, Telomerase, and Senescence、interferon and immune responses

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 apop...