Acquired Chemoresistance in Colorectal Cancer: Therapy-Induced Signalling Adaptation, Cellular Plasticity and Mechanism-Guided Therapeutic Strategies

The effectiveness of chemotherapy in colorectal cancer (CRC) is significantly reduced by acquired chemoresistance to 5-fluorouracil (5-FU), oxaliplatin and irinotecan. This structured narrative review synthesises mechanistic, preclinical, translational and clinical evidence underlying resistance to these agents. Distinct drug-specific molecular mechanisms can underlie acquired chemoresistance, whereas shared adaptive survival processes support treatment persistence and may, in some settings, contribute to the emergence of stable acquired resistance. 5-FU resistance is associated with factors such as altered thymidylate synthase activity, drug catabolism, nucleotide metabolism and apoptosis avoidance, whereas resistance to oxaliplatin involves enhanced deoxyribonucleic acid (DNA) repair, detoxification, reduced platinum accumulation and metabolic adaptation. Irinotecan resistance can involve reduced TOP1 expression or TOP1 mutations, altered SN-38 metabolism, increased drug efflux and enhanced tolerance of replication-associated stress. Alongside these drug-proximal mechanisms, drug-tolerant persister states, stem-like programmes, epithelial–mesenchymal plasticity and multidrug-efflux mechanisms can support treatment survival and tumour repopulation. Evidence linking chemoresistance with Wnt/β-catenin, Notch and Hippo/Yes-associated protein 1 (YAP1) signalling is predominantly preclinical and varies according to treatment context, with stronger direct pathway-specific evidence for 5-FU and oxaliplatin than for irinotecan. This distinction allows direct drug-specific associations to be differentiated from broader roles in adaptive survival, cellular plasticity and tumour repopulation after treatment. Cancer-associated fibroblasts, immune and cytokine signalling, extracellular vesicles, hypoxia and treatment-induced remodelling of the tumour microenvironment can all further influence tumour heterogeneity and non-cell-autonomous resistance. Residual disease, resistant cellular states and therapeutically relevant molecular dependencies may be detected or characterised using circulating tumour DNA, pathway-associated biomarkers, patient-derived organoids and emerging resistance-profiling technologies. These findings show that interactions between drug-specific molecular escape mechanisms, adaptive cellular states and the tumour microenvironment contribute to heterogeneous patterns of treatment survival and acquired chemoresistance. The development of molecularly targeted and mechanism-guided strategies for overcoming resistance in CRC may be supported by defining these mechanisms and their associated biomarkers.