Cancer Stem Cell Quiescence: Molecular and Microenvironmental Evidence for an Actively Regulated Adaptive Survival Strategy.

Cancer stem cells (CSCs) are a therapy-refractory subpopulation that drives tumor persistence, recurrence, and metastasis. A defining characteristic of CSCs is their ability to reversibly exit the cell cycle and enter a quiescent state, thereby escaping cytotoxic therapies that primarily target proliferating cells. Although numerous reviews have examined CSC dormancy and quiescence, less attention has been devoted to recently identified regulators and to the molecular events associated with the transition into quiescence. This narrative review consolidates current knowledge on CSC-specific entry regulators, including the pRb/RBL2-E2F1/4-GCN5 axis, Fbxw7-c-Myc pathway, PML-PPARδ-FAO axis, ID1/ID3-p21 network, JARID1B-mediated G0-like states, CDH1-SIRT5-Cyclin F axis, and AP-1/ETS network, alongside emerging evidence on epigenetic regulation, circadian influences, and immune-mediated signals. We critically evaluate the exhaustion hypothesis, delineate a therapeutic framework that distinguishes between prevention of quiescence entry, elimination of dormant CSCs, and forced reactivation, and identify key knowledge gaps. By integrating recent advances within a structured perspective, this review provides a framework for understanding how CSCs exploit quiescence for survival and therapy resistance and informs strategies to target this resilient population.