Drug-tolerant persistent (DTP) cells have emerged as a reversible, slow-cycling survival state that enables early therapeutic tolerance and underlies the development of stable resistance in all types of cancer. To comprehensively characterize this phenomenon, we conducted a PRISMA-ScR-guided exploratory review across four major databases (PubMed, Scopus, Web of Science, Dimensions), identifying 343 eligible records spanning 2010-2025. In all experimental systems, including 2D cell lines, spheroids, organoids, xenografts, residual disease models, and clinical samples, DTP cells consistently showed survival under high drug concentrations or prolonged exposure, depending on non-genetic adaptive programs, and recovery of proliferative potential and drug sensitivity after treatment cessation. Analysis of the molecular mechanisms revealed a convergence of reversible pathways involving apoptosis escape, quiescence, chromatin remodeling, phenotypic plasticity, metabolic rewiring, downstream survival signaling, and transient programs, such as those of stem cells. These findings support a model in which DTP cells represent an early and plastic node within a broader continuum of resistance, capable of progressing toward genetically fixed resistance through stress-induced mutagenesis. Methodological heterogeneity among studies did not diminish the reproducibility of DTP cells fundamental characteristics but underscored the need for standardized experimental criteria. Notably, the integrated evidence identifies therapeutically exploitable vulnerabilities—epigenetic, metabolic, signaling-based, and plasticity-targeted—that have shown promise in reducing DTP persistence and delaying the development of resistance. This review consolidates current knowledge and provides a mechanistic framework to guide therapeutic strategies that aim to intercept cancer resistance in the earliest and most reversible stages of its development.
Lopez-Gonzalez et al. (Wed,) studied this question.