Targeting Drug-Tolerant Persister Cancer Cells: Can Nanomaterial-Based Strategies Be Helpful for Anti-DTP Therapies?

Therapeutic resistance remains a critical barrier in oncology, frequently leading to cancer relapse after initial treatment response. Growing evidence suggests the presence of drug-tolerant persisters (DTPs), a rare subpopulation of cancer cells that survives chemotherapy by entering a reversible specific adaptation. Unlike classical cell resistance, the DTP phenotype is independent of genetic changes and maintained through dynamic regulatory mechanisms. DTPs are phenotypically heterogeneous and can exhibit stem-like and quiescent cell phenotypes, non- or slow proliferation, and remarkable plasticity due to a di-pause-like state and executing epithelial-mesenchymal transition (EMT) or transdifferentiation processes. Despite advances in research, the molecular mechanisms underlying DTPs' biology and their role in cancer relapse remain only partially understood. The review summarizes the current progress in processes that lead to the acquisition of cellular persistence status, which, in turn, constitute areas of vulnerability that can be exploited in cancer therapy. We highlight anti-DTP therapeutic strategies, including epigenetic modification, cell signaling and transcriptional regulation, metabolic reprogramming, and modification of cell interactions within the tumor microenvironment. Furthermore, we focus on the potential role of nanomaterials in the combat against DTPs. Nanoparticles not only act as part of the drug delivery process, enabling precise DTP targeting and enhancing intracellular drug accumulation, but their intrinsic properties can also be used to eradicate DTPs directly or by enhancing the effectiveness of other therapeutic strategies. The integrated approach offers strong potential to eliminate tumor persistence, prevent recurrence, and improve long-term patient outcomes beyond conventional therapies.