Brain metastasis-associated cancer fibroblasts drive tumor progression and therapeutic resistance through IL26 and CX3CL1 signaling in non-small-cell lung cancer.

Brain metastases (BM) from non-small cell lung cancer (NSCLC) represent a significant clinical challenge, characterized by poor prognosis and treatment resistance. While cancer-associated fibroblasts (CAFs) are recognized as crucial components of the BM tumor microenvironment (TME), their mechanistic contributions to disease progression and therapeutic resistance remain poorly understood. In this study, we demonstrated that patient-derived BM-CAFs significantly enhanced NSCLC cell proliferation, migration, invasion and therapeutic resistance in vitro. Mechanistically, BM-CAFs promoted epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) phenotypes through upregulation of key transcription factors. In-vivo experiments showed that co-injection of NSCLC cells with BM-CAFs accelerated tumor growth and enhanced cisplatin resistance. Molecular analysis revealed these effects were mediated through distinct mechanisms whereby IL26 activated the JAK-STAT3 pathway, while CX3CL1 activated both JAK-STAT3 and AKT-mTOR pathways. Importantly, neutralizing antibodies against IL26 and CX3CL1 effectively suppressed their respective signaling pathways and reversed EMT and CSC characteristics. In summary, our findings establish the IL26 and CX3CL1 signaling as a critical mediator of BM-CAF-induced tumor progression and therapy resistance in NSCLC BM, suggesting a potential therapeutic strategy for this challenging disease.