Targeting Drug-Tolerant Persister Cells in Cancer: Progress From Modeling to Targeting Fragility Studies

Drug-tolerant persister (DTP) cells are a major cause of cancer treatment failure and tumor relapse. This review provides a systematic summary of recent advances in research on DTP cells in cancer, including their biological features, model systems, and targeting strategies. Current studies show that formation of DTP cells is a complex and dynamic process, involving cell cycle arrest, epigenetic remodeling, and extensive transcriptional and metabolic reprogramming. The drug tolerance of DTP cells arises from a cooperative molecular network that integrates metabolic adaptation, reactivation of key signaling pathways, and resistance to cell death programs. To investigate the DTP state, researchers have developed a variety of in vitro and in vivo models, including patient-derived xenograft (PDX) models, drug-treated cancer cell lines, and organoid systems. These models have become essential tools for identifying vulnerabilities in DTP cells, such as sensitivity to ferroptosis induction, dependence on specific metabolic pathways, and expression of distinct surface antigens. However, the field still faces important challenges. Existing models have limitations in mimicking the complex tumor microenvironment and in capturing the transient nature of DTP cells. In addition, the clinical value of targeting strategies identified with experimental models remains to be validated in large-scale trials. The high level of heterogeneity of DTP cells and the lack of standardized research protocols also hinder the comparison and integration of findings across studies. The future development of more physiologically relevant models, the use of advanced technologies to better characterize DTP cells, and the design of clinical trials aimed at eliminating DTP cells are critical steps in the transition from tumor control to durable cure.