Dedifferentiation of mature tumor cells into cancer stem cells as a driver of tumor evolution

Tumor evolution is a dynamic and multifactorial process driven by genetic alterations, epigenetic remodeling, and adaptive responses to environmental pressures. A central concept emerging from recent cancer research is the role of cellular plasticity in shaping tumor heterogeneity and therapeutic resistance. In particular, the dedifferentiation of mature tumor cells into cancer stem cells (CSCs) has been increasingly recognized as a major mechanism contributing to tumor progression and adaptation. Rather than representing a fixed population derived exclusively from normal stem cells, CSCs are now understood as a dynamic cellular state that can be acquired or lost through reversible phenotypic transitions. These transitions are regulated by complex networks involving transcriptional reprogramming, epigenetic modifications, developmental signaling pathways, and microenvironmental signals. Importantly, dedifferentiation allows differentiated tumor cells to regain stem-like properties, thereby replenishing the CSC pool and facilitating tumor evolution. This review integrates the classical clonal evolution model with the cancer stem cell framework, proposing that dedifferentiation represents a key non-genetic engine of tumor evolution. We discuss the molecular mechanisms underlying CSC plasticity, the role of epithelial–mesenchymal transition, epigenetic reprogramming, and microenvironmental signals in driving dedifferentiation. Furthermore, we examine evidence from single-cell transcriptomics and lineage-tracing studies demonstrating dynamic cell state transitions within tumors. Finally, we explore the implications of CSC plasticity for metastasis, therapy resistance, and future therapeutic strategies targeting tumor evolution.