Cancer-associated fibroblast derived CXCL14 drives cisplatin chemoresistance by enhancing nucleotide excision repair in bladder 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-secreted CXCL14 engaged CCR7 on bladder Cancer cells, triggering STAT3 phosphorylation and consequently upregulating the DNA repair gene ERCC4 to promote cisplatin resistance. In vivo validation confirmed that pharmacological CCR7 or STAT3 inhibition markedly reversed chemoresistance and potentiated cisplatin-induced tumor cell death. Notably, STAT3 activation mediated the overexpression of the glycolytic Enzymes HK2 and LDHA, resulting in greater glycolytic flux in resistant cells. This metabolic reprogramming further facilitated the transdifferentiation of normal fibroblasts into CXCL14-secreting CAFs, establishing a self-reinforcing feedback loop that sustains chemoresistance.

Conclusion: The CXCL14/CCR7/STAT3 axis critically mediates cisplatin resistance in bladder Cancer through dual modulation of DNA repair and glycolytic metabolism. Therapeutic cotargeting of this pathway with CCR7 or STAT3 inhibitors combined with cisplatin represents a promising strategy to overcome chemoresistance and improve clinical outcomes.

Bladder cancer; CXCL14; Cancer-associated fibroblast; Chemoresistance; DNA damage repair.