Cancer stem cells in focus: Deciphering the dynamic functional landscape of stemness in cancer

Abstract

Cancer stem cells (CSCs) are central to tumour initiation, progression, and relapse, yet their dynamic and adaptive nature hampers therapeutic targeting. Once viewed as a fixed subpopulation, CSCs are now recognised as a fluid functional state that tumour cells can enter or exit, driven by intrinsic programs, epigenetic reprogramming, and microenvironmental cues. This plasticity complicates identification due to inconsistent marker expression and enables resistance, dormancy, and metastasis. Epigenetic regulators and miRNAs further reinforce stemness under therapeutic stress, keeping the CSC concept contested. Despite promising preclinical efforts, clinical translation of CSC-targeted therapies remains limited by inadequate models and incomplete understanding of CSC-state transitions. This review examines CSC heterogeneity and regulation, while highlighting limitations of current markers and models. We propose that not all committed cancer cells sustain tumour growth; rather, a subset with stem-competent potential may dedifferentiate into CSCs. Finally, we propose future directions to define actionable vulnerabilities and improve CSC-directed therapies.