Multidimensional regulatory networks of drug resistance in colorectal cancer: from molecular mechanisms to novel therapeutic counterstrategies.

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, and the widespread occurrence of drug resistance constitutes a central bottleneck that constrains therapeutic efficacy and adversely affects long-term patient outcomes. Current therapeutic strategies, guided by the Tumor-Node-Metastasis (TNM) staging system, integrate chemotherapy, targeted therapy, and immunotherapy; however, resistance frequently limits their long-term efficacy. This review adopts a stage-oriented, pharmacology-driven framework to systematically integrate resistance mechanisms and corresponding counterstrategies across CRC management. We analyze resistance across major therapeutic modalities, including chemotherapeutics (5-fluorouracil, oxaliplatin, irinotecan), targeted agents (epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors), and immune checkpoint inhibitors, with mechanistic insights directly linked to actionable, mechanism-guided interventions-including novel targeted agents, rational combination strategies, nanomedicine-based delivery systems, and emerging immunotherapeutic approaches. We further highlight convergent mechanisms that transcend individual therapies, particularly cancer stem cell plasticity and epigenetic reprogramming, which collectively drive multidrug resistance (MDR). Finally, in conjunction with emerging resistance detection technologies such as circulating tumor DNA (ctDNA), this review explores future directions for resistance monitoring and precision treatment adaptation, aiming to provide a systematic reference for overcoming therapeutic resistance in CRC.