Cancer drug-tolerant persister cells: from biological questions to clinical opportunities

Abstract

The emergence of drug resistance is the most substantial challenge to the effectiveness of anticancer therapies. Orthogonal approaches have revealed that a subset of cells, known as drug-tolerant 'persister' (DTP) cells, have a prominent role in drug resistance. Although long recognized in bacterial populations which have acquired resistance to antibiotics, the presence of DTPs in various cancer types has come to light only in the past two decades, yet several aspects of their biology remain enigmatic. Here, we delve into the biological characteristics of DTPs and explore potential strategies for tracking and targeting them. Recent findings suggest that DTPs exhibit remarkable plasticity, being capable of transitioning between different cellular states, resulting in distinct DTP phenotypes within a single tumour. However, defining the biological features of DTPs has been challenging, partly due to the complex interplay between clonal dynamics and tissue-specific factors influencing their phenotype. Moreover, the interactions between DTPs and the tumour microenvironment, including their potential to evade immune surveillance, remain to be discovered. Finally, the mechanisms underlying DTP-derived drug resistance and their correlation with clinical outcomes remain poorly understood. This Roadmap aims to provide a comprehensive overview of the field of DTPs, encompassing past achievements and current endeavours in elucidating their biology. We also discuss the prospect of future advancements in technologies in helping to unveil the features of DTPs and propose novel therapeutic strategies that could lead to their eradication.

Fig. 1 |. The key features of drug-tolerant persister cells.

Numerous studies have shown that drug-tolerant persisters (DTPs) can rewire multiple cellular functions (from the epigenome to transcription to translation to metabolism) and manipulate the surrounding microenvironment to promote their survival. Moreover, the phenotypic and genetic adaptability of DTPs are increasingly regarded as key drivers of tumour relapse under cancer treatment^{,,,,,–,,,,–,,}. ALDH, aldehyde dehydrogenase; APOBEC, apolipoprotein B mRNA editing enzyme catalytic polypeptide-like; CAF, cancer-associated fibroblast; ECM, extracellular matrix; eIF4A, eukaryotic initiation factor 4A; EMT, epithelial-to-mesenchymal transition; FAO, fatty acid β-oxidation; GPX4, glutathione peroxidase 4; IGF1R, insulin-like growth factor 1 receptor; JAK, Janus kinase; KDM5/6, lysine demethylase 5/6; LINE1, long interspersed repeat element 1; m⁶A, N⁶-methyladenosine; MITF, microphthalmia-associated transcription factor; OXPHOS, oxidative phosphorylation; Pol II, polymerase II; PuMB, purine mutational bias; STAT3, signal transducer and activator of transcription 3; TAM, tumour-associated macrophage; TCR, T cell receptor; TEAD, TEA domain family member; YAP, yes-associated protein.

Fig. 2 |. Drug-tolerant persister cells rewire their microenvironment to escape immunity and survive.

A complex secretory interplay among drug-tolerant persisters (DTPs), the extracellular matrix (ECM) and the other elements of the tumour microenvironment (encompassing macrophages, fibroblasts and inflammatory cells) promotes the dormancy and survival of DTPs under treatment and, ultimately, enhances their escape from the immune system^–,–. CAF, cancer-associated fibroblast; FAK, focal adhesion kinase; FGF2, fibroblast growth factor 2; HGF, hepatocyte growth factor; IFNγ, interferon-γ; IGF1, insulin-like growth factor 1; IL-6, interleukin-6; MET, mesenchymal-to-epithelial transition; MHC, major histocompatibility complex; PDL1, programmed cell death protein 1 ligand 1; TAM, tumour-associated macrophage; TCR, T cell receptor; TGFβ, transforming growth factor-β.

Fig. 3 |. Therapeutic strategies to prevent tumour relapse from drug-tolerant persister cells.

a, Drug-tolerant persisters (DTPs) emerging under treatment (possibly from predestined ‘pre-DTP’ cells) activate different strategies to adapt their phenotype in a plastic manner and evolve their genotype. The resulting adapted cells with (epi) genetic mechanisms of resistance are then further selected. b, The identification of a vulnerability of DTPs can drive the design of innovative therapeutic approaches to eradicate them, possibly preventing tumour relapse. Treatments targeting pre-DTP cells would be administered concomitantly with standard-of-care treatment, whereas drugs tackling specific vulnerabilities and/or adaptability of DTPs could be administered as part of a sequential strategy. Finally, pulsatory regimens could be designed to maintain a stable reservoir of sensitive cancer cells throughout treatment. CAF, cancer-associated fibroblast; TAM, tumour-associated macrophage.