• Chemoresistance in CRC is multifactorial, involving drug efflux, DNA repair, apoptosis evasion, and epigenetic changes.
• Cancer stem cells and the tumor microenvironment significantly contribute to resistance and tumor relapse.
• Novel therapeutic strategies, including targeted therapy and immunotherapy, show promise in overcoming resistance.
• Personalized medicine and biomarker-guided treatment are essential for improving outcomes in chemoresistant CRC.