Cancer Stem Cells in Colorectal Cancer: From Molecular Mechanisms to Diagnosis, Prognosis and Therapy Implications

Colorectal cancer (CRC) remains a major cause of cancer-related mortality, with recurrence and treatment resistance as persistent challenges. Increasing evidence supports the cancer stem cell (CSC) model in CRC, in which a subpopulation of self-renewing colorectal cancer stem cells (CCSCs) sustains tumor growth, metastasis, and therapy resistance. CCSCs are increasingly recognized as key drivers of tumor progression, therapeutic resistance, and relapse, and are increasingly being investigated not only as therapeutic targets but also as biomarkers with diagnostic and prognostic relevance in CRC. Multiple signaling pathways regulate CCSC maintenance and aggressive behavior, including Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT, MAPK/ERK, NF-κB, and TGF-β signaling. These pathways form the basis of therapeutic strategies aimed at modulating stemness-associated pathways, with several CSC-focused agents and pathway inhibitors currently under translational and clinical investigation. In parallel, CCSC surface markers and molecular signatures are being explored as putative tools for early detection, minimal residual disease monitoring, and outcome prediction. However, successful translation of CSC-directed approaches into effective and safe clinical applications remains difficult. Tumor heterogeneity, CSC plasticity, compensatory signaling mechanisms, and the shared regulatory networks between malignant and normal intestinal stem cells pose substantial barriers. In this review, we summarize the molecular mechanisms underlying CCSC biology, discuss their diagnostic and prognostic implications. We also focus on clinical trials that apply CCSC-directed therapeutic, biomarker, and prevention strategies in CRC., Finally, we emphasize the lessons learned and the translational challenges, including the need for rigorously validated, CCSC-specific biomarkers, that continue to shape the development of these therapeutic and biomarker strategies.