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In this study, we aimed to investigate the molecular and phenotypic mechanisms underlying irinotecan resistance in CRC using the LIM1215 cell line model. Transcriptomic analysis demonstrated that drug withdrawal induced major transcriptional reprogramming, characterized by downregulation of ABC transporters (ABCB1 and ABCG2), extracellular matrix\u2010related genes, and markers of epithelial\u2010to\u2010mesenchymal transition (EMT), alongside reactivation of cell cycle pathways. Drug screening further indicated that resistant cells maintained under irinotecan pressure exhibited a multidrug\u2010resistant phenotype, while withdrawn cells regained sensitivity, particularly to tyrosine kinase inhibitors. 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