Abstract
BACKGROUND: Chemoresistance induced by cancer-associated fibroblasts (CAFs) is well recognized, yet its mechanisms remain unclear and no CAF-targeted therapies are available. Gastric cancer (GC) with extensive CAF infiltration correlates with poor prognosis, and emerging evidence highlights the GAS6/AXL axis in CAF-GC interactions. This study targets GAS6/AXL axis to overcome CAF-mediated chemoresistance and enhance chemotherapy efficacy. METHODS: We investigated the effect of 9im, a selective AXL inhibitor, on CAF-induced chemoresistance in GC using transwell migration, western blotting, viability assays, flow cytometry, drug efflux assays and in vivo experiments. Transcriptome analysis identified chemoresistance-related genes, and luciferase assays assessed STAT3 binding to the ABCG1 promoter. RNA-ISH analyzed GAS6 (+) CAFs in GC samples, while public data evaluated the prognostic significance of ABCG1 and CAF markers. RESULTS: GAS6 expression was elevated in CAF. CAF-derived GAS6 promoted GC cell migration and chemoresistance via AXL activation, effects reversed by 9im. STAT3 bound to the ABCG1 promoter, enhancing expression, while STAT3 inhibition reduced ABCG1 levels. 9im restored chemosensitivity in GC models. Clinically, ABCG1 and CAF marker co-expression correlated with poor prognosis. CONCLUSIONS: CAF-derived GAS6 induces GC chemoresistance via the AXL/STAT3/ABCG1 pathway. 9im restores chemosensitivity by inhibiting AXL and ABCG1-mediated efflux. AXL inhibitors with chemotherapy may improve GC treatment.