Erasing the invisible: targeting persister cells to cure minimal residual disease

Abstract Despite revolutionary advances in immunotherapy and targeted therapies, tumor recurrence driven by minimal residual disease (MRD) and drug-tolerant persister (DTP) cells remains a critical challenge in oncology. MRD, a reservoir of residual cancer cells undetectable by conventional imaging but identifiable via sensitive molecular techniques like next-generation sequencing and ctDNA analysis, serves as a prognostic biomarker for relapse across hematologic and solid malignancies. Within MRD, DTP cells, characterized by transient drug tolerance, evade therapies through adaptive mechanisms such as quiescence, metabolic reprogramming, epigenetic modifications, and signaling pathway activation. These cells, pivotal in mediating therapeutic resistance, dynamically evolve from reversible tolerance to stable resistance, fueling disease relapse. This review elucidates the clinical significance of MRD and DTP cells, detailing their biological characteristics, detection technologies, and formation mechanisms. We highlight therapeutic strategies targeting DTP cells, including pathway inhibitors, epigenetic modulators, and autophagy blockers, to reverse MRD and prevent recurrence. Challenges in translating these approaches to clinical practice, such as DTP heterogeneity and biomarker development, are addressed alongside emerging technologies like single-cell omics and AI-driven analytics. By integrating mechanistic insights with innovative detection and therapeutic strategies, targeting DTP cells within MRD holds transformative potential to enhance long-term cancer outcomes.