Abstract: Background and purpose: Chemotherapy resistance is an important factor resulting in poor prognosis of gastric cancer patients. The elucidation of molecular mechanisms underlying chemoresistance is helpful to provide new therapeutic strategy, which has important practical significance. This study aimed to investigate the effect ofexosomal miR-223 derived from macrophage on oxaliplatin chemosensitivity of gastric cancer cells and its mechanism. Methods: Gastric cancer cells purchased from National Collection of Authenticated Cell Cultures were co-cultured with macrophages or macrophage-derived exosomes. The miR-223 expression was detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR). The transfer of miR-223 through internalization of exosomes was observed by immunofluorescence. Macrophages were transfected with a miR-223 inhibitor or negative control. Cell counting kit-8 (CCK-8) and apoptosis assay were employed to explore the effect of macrophage-derived exosomes on the oxaliplatin chemosensitivity of gastric cancer cells. The clinical relationship between the expression of exosomal miR-223 in plasma and oxaliplatin resistance in gastric cancer patients was also explored. Results: The chemosensitivity of gastric cancer cells to oxaliplatin decreased, while half inhibition concentration (IC ₅₀ ) increased significantly when co-cultured with macrophages or macrophage-derived exosomes. The expression level of miR-223 was significantly increased, and exosomal transfer of miR-223 was observed by immunofluorescence. Functional studies revealed that exosomal miR-223 derived from macrophages promoted oxaliplatin resistance in gastric cancer cells by inhibiting FBXW7. Clinically, the high expression of plasma exosomal miR-223 was highly linked with oxaliplatin resistance in gastric cancer patients. Conclusion: The exosomal transfer of macrophage-derived miR-223 conferred oxaliplatin resistance in gastric cancer cells, and these results indicated that circulating exosomal miR-223 may be a useful monitoring indicator for oxaliplatin resistance in gastric cancer treatment.

Key words: Macrophage, Gastric cancer, Exosome, miR-223, Oxaliplatin, Chemoresistance