• CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells, and its overexpression diminishes sensitivity to EGFR-TKIs.
• Suppression of CCL2 via bindarit or knockdown reverses EGFR-TKIs resistance and reduces EMT marker expression.
• CCL2 promotes EGFR-TKIs resistance through activation of the AKT-EMT signaling pathway.
• Targeting CCL2 represents a promising therapeutic strategy to overcome acquired EGFR-TKIs resistance in NSCLC.