Cancer stem cells in personalized therapy: mechanisms, microenvironment crosstalk, and therapeutic vulnerabilities

Cancer stem cells (CSCs) drive tumor progression, therapy resistance, and metastasis through unique membrane biology, glycosylation patterns, and metabolic adaptations. CSCs exhibit a distinct glycocalyx profile enriched in hyaluronan, heparan sulfate, and sialylated glycans, facilitating immune evasion, adhesion, and survival. Key signaling pathways—Wnt/β-catenin, Hedgehog, Notch, JAK/STAT, TGF/SMAD, and PI3K/AKT/mTOR—regulate CSC stemness and therapeutic resistance. Emerging biomarkers (CD44, CD133, ALDH1, EpCAM) and targeted therapies (CAR-T cells, miRNA modulation, lipid metabolism inhibitors) show promise in disrupting CSC resilience. Advances in single-cell omics, CRISPR screening, and patient-derived organoids (PDOs) enhance CSC characterization and precision medicine applications. However, challenges remain in standardizing organoid cultures, replicating tumor microenvironments, and overcoming CSC plasticity. Integrating CSC-targeted strategies with conventional therapies may improve clinical outcomes by eradicating therapy-resistant populations and preventing relapse. This review underscores the need for innovative combination therapies to eradicate CSCs and improve clinical outcomes, while addressing challenges in biomarker validation, therapeutic resistance, and translational applications.