Epigenetic and RNA control of cancer stem cell plasticity and therapy resistance

Cancer stem cell (CSC) plasticity and therapy resistance involve chromatin regulation, RNA modifications, and noncoding RNA circuits that differ in their mechanisms and evidential support. This review distinguishes functionally defined CSCs from marker-defined stem-like populations and drug-tolerant persisters (DTPs), which can overlap while retaining different defining properties. We synthesize DNA and histone modifications, chromatin organization, m 6 A and m 6 Am regulation, and noncoding RNAs, including extracellular-vesicle-mediated RNA trafficking. RNA-mediated signaling and intercellular transfer are classified separately where evidence for a chromatin or RNA-modification mechanism is lacking. A claim-specific E1–E4 framework separates human evidence with functional validation, causal in vivo experiments, cell-based functional stemness assays, and associations; developmental stage is assessed independently. Conflicting glioblastoma RNA-modification studies and the opposing effects of FTO across tumor contexts show that therapeutic direction depends on more than regulator identity. Longitudinal acute myeloid leukemia studies support regulatory-state heterogeneity at relapse, while a universal CSC-specific epigenetic cause remains unproven. Metabolic and niche examples are evaluated according to the measured regulatory change, rescue experiments, functional stemness assays, and treatment endpoints. Translation requires separate measures of target engagement, cell-state redistribution, and sustained loss of tumor-propagating capacity, together with normal-stem-cell and long-term safety assessment. This framework identifies testable therapeutic dependencies and defines the evidence needed to support claims of CSC eradication.