Cancer-associated fibroblast derived CXCL14 drives cisplatin chemoresistance by enhancing nucleotide excision repair in bladder cancer

作者：Tinghao Li, Kunyao Zhu, Hang Tong, Yan Sun, Junlong Zhu, Zijia Qin, Junrui Chen, Linfeng Wu, Xiaoyu Zhang, Aimin Wang, Xin Gou, Hubin Yin, Weiyang He · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03487-4 · 被引用次数：14 · 研究领域：Chemokine receptors and signaling、Cancer Cells and Metastasis、Immune cells in cancer

BACKGROUND: A significant challenge in bladder cancer treatment is primary chemoresistance, in which cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a pivotal role. While the contributions of CAFs to tumor progression and drug resistance are well established, the precise molecular mechanisms by which they induce chemoresistance remain unclear. A comprehensive understanding of the effect of TME modulation-particularly through CAFs-on the chemotherapeutic response is crucial for developing effective strategies to overcome chemoresistance and improve patient survival. METHODS: Primary fibroblasts were isolated from paired clinical samples of bladder cancer tissues and adjacent normal tissues to identify key CAF-derived secretory factors. Bioinformatics analysis, semiquantitative RT‒qPCR, and dual-luciferase reporter assays were subsequently used to investigate the functional role and mechanistic basis of CXCL14 in chemoresistance. The therapeutic relevance of these findings was further evaluated through in vitro and in vivo models, including ex vivo patient-derived organoid (PDO) models, by assessing cisplatin sensitivity and validating therapeutic targeting of the CXCL14-CCR7-STAT3 axis with small molecule inhibitors. RESULTS: Compared to normal fibroblasts and CAFs from nonchemoresistance groups, CAFs derived from cisplatin-resistant patients demonstrated significantly greater paracrine-mediated induction of chemoresistance. Mechanistically, CAF-s...