Abstract
Colorectal cancer (CRC) remains a major global health burden, with therapeutic resistance accounting for the majority of treatment failures and cancer-related deaths. Cancer stem cells (CSCs), which possess intrinsic drug tolerance and self-renewal capacity, drive both primary and acquired resistance. CSCs maintain drug tolerance through the activation of core signaling cascades, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt, and MAPK/ERK pathways, as well as through epithelial-mesenchymal transition (EMT), enhanced DNA repair, and PD-1/PD-L1-mediated immune evasion. These molecular alterations transform the tumor microenvironment (TME) into a stemness-supportive, immunosuppressive niche, thereby promoting tumor recurrence and metastasis. Recent advances in CSCs-directed therapy include monoclonal antibodies targeting stem cell surface antigens, small-molecule inhibitors that disrupt self-renewal pathways, epigenetic agents that reprogram stemness, and immunotherapies aimed at reactivating anti-tumor immune surveillance. Emerging multi-drug regimens that combine CSCs-targeted agents with chemotherapy, pathway inhibitors, or immune checkpoint blockade exhibit synergistic efficacy by simultaneously disrupting multiple resistance mechanisms. Additionally, nanotechnology-based delivery systems further improve drug bioavailability and tumor specificity while reducing systemic toxicity. Despite notable progress, substantial challenges remain, including the pronounced heterogeneity of CSCs, activation of compensatory signaling pathways, and the lack of robust biomarkers for CSCs identification and therapeutic monitoring. Future research should prioritize integrative multi-omics approaches to delineate CSCs-specific vulnerabilities, the rational development of synergistic combination therapies, and the efficient clinical translation of CSCs-directed strategies. This review aims to describe the molecular mechanisms of CSCs-driven drug resistance in CRC, highlighting the current and emerging therapeutic strategies to guide the development of more effective, personalized interventions.