BIONATURE

Cancer stem cells (CSCs) represent a distinct subpopulation within malignant tumours that drive tumour growth, resist treatment, and seed metastatic disease through their capacity for self-renewal and multipotent differentiation. Their discovery has shifted how the field thinks about tumour heterogeneity and therapeutic failure. At the molecular level, CSC identity depends on a network of signalling pathways — Wnt/β-catenin, Notch, Hedgehog, PI3K/AKT/mTOR, and JAK/STAT3 — that sustain the expression of stemness transcription factors such as NANOG, OCT4, and SOX2. Epigenetic mechanisms, including DNA methylation, Polycomb-mediated histone modification, and non-coding RNA networks, reinforce these programmes and give CSC identity a stability that goes beyond genetic mutation. The tumour microenvironment supplies critical extrinsic support through hypoxic niches, cancer-associated fibroblasts, tumour-associated macrophages, and perivascular structures, all of which help CSCs evade immune clearance. The epithelial–mesenchymal transition further enables non-CSC tumour cells to acquire stem-like properties in response to stress, complicating simple hierarchical models of tumour organisation. Together, these features render CSCs intrinsically and adaptively resistant to chemotherapy, radiotherapy, and most targeted agents, making them the primary substrate of disease recurrence and distant spread. Therapeutic strategies to eliminate CSC populations are now advancing rapidly, ranging from surface marker-directed antibodies and CAR T cell therapies to epigenetic reprogramming agents, small-molecule pathway inhibitors, immune checkpoint combinations, and metabolic interventions. This review synthesises current mechanistic understanding of CSC biology and critically evaluates the therapeutic landscape, with attention to both promising advances and persistent challenges.