Drug-tolerant persister (DTP) cell populations were originally discovered in antibiotic-resistant bacterial biofilms. Similar populations with comparable features have since been identified among cancer cells and have been linked with treatment resistance that lacks an underlying genomic alteration. Research over the past decade has improved our understanding of the biological roles of DTP cells in cancer, although clinical knowledge of the role of these cells in treatment resistance remains limited. Nonetheless, targeting this population is anticipated to provide new treatment opportunities. In this Perspective, we aim to provide a clear definition of the DTP phenotype, discuss the underlying characteristics of these cells, their biomarkers and vulnerabilities, and encourage further research on DTP cells that might improve our understanding and enable the development of more effective anticancer therapies.
Drug-tolerant persister (DTP) cells are phenotypically heterogeneous, with diverse characteristics such as slow-proliferating or quiescent phenotypes, and a range of metabolic adaptations, cell identity switches and immune-evasion mechanisms. The specific traits expressed depend on the type of cancer and the treatment received.
DTP cells arise stochastically. All cancer cells have the potential to enter a drug-tolerant state depending on their initial adaptive response to treatment.
The DTP cell phenotype is transient and does not reflect the presence of resistance mutations. These cells can either produce drug-sensitive progeny or evolve towards irreversible, acquired resistance mediated by acquired genomic alterations.
DTP cells emerge in tumours that initially respond to systemic anticancer therapies and might not be involved in disease recurrence following local therapies such as surgery. Incomplete responses to systemic therapies might reflect the coexistence of several distinct populations of resistant cancer cells, including dormant tumour cells, cancer stem cells, clones harbouring primary resistance and DTPs.
No universally accepted biomarkers enabling the identification of DTP cells currently exist. The roles of DTP cells should be investigated in the context of specific clinical scenarios to facilitate their optimal application in precision oncology.
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S.S. acknowledges grant support from the National Natural Science Foundation of China (grant No. 82172794) and from the National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (grant No. Y2022JC002). C.R. thanks S. Bazin, O. and C. Courtin, Ensemble Contre le Mélanome, the Foundation Crédit Mutuel, Foundation Carrefour and the association Vaincre le Mélanome for their ongoing research funding support.
C.R. has acted as a consultant for Astra Zeneca, BMS, MSD, Pfizer, Pierre Fabre, Roche, and Sanofi and is a co-founder of Ribonexus. Y.P., L.L., H.P., L.L., D.H., F.V. and S.S. declare no competing interests.
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Pu, Y., Li, L., Peng, H. et al. Drug-tolerant persister cells in cancer: the cutting edges and future directions. Nat Rev Clin Oncol 20, 799–813 (2023). https://doi.org/10.1038/s41571-023-00815-5