化学治疗剂的使用以及过去几十年中新的癌症疗法的研发，导致了无数治疗抵抗机制的出现。曾经认为这些机制完全受遗传因素驱动，但在一些肿瘤中可逆敏感性和无预先存在的突变的耦合导致了药物耐受持久靶细胞的发现（drug-tolerant persisters，DTPs）：这些耐药的细胞亚群在慢速分裂，表现出对治疗的可逆敏感性。这些细胞赋予靶向和化疗的多重药物耐受性，直到残留疾病能够建立稳定的耐药状态。DTP状态可以利用多种不同但相互交织的机制来生存，避免致命药物的暴露。在这里，我们将这些多方面的防御机制归类为癌症耐药性的独特特征。在最高层面上，这些特征由异质性、信号可塑性、分化、增殖/代谢、应激管理、基因组完整性、与肿瘤微环境的相互作用、免疫逃逸和表观遗传调控机制组成。其中，表观遗传学既是非遗传性抵抗的首个提出手段之一，也是最早被发现的手段之一。正如我们在本文中所描述的那样，表观遗传调控因素涉及到DTP生物学的大多数方面，将这个特征定位为药物耐受性的全面中介和新疗法的潜在途径。版权所有©2023 Elsevier Inc.。保留所有权利。

The use of chemotherapeutic agents and the development of new cancer therapies over the past few decades has consequently led to the emergence of myriad therapeutic resistance mechanisms. Once thought to be explicitly driven by genetics, the coupling of reversible sensitivity and absence of pre-existing mutations in some tumors opened the way for discovery of drug-tolerant persisters (DTPs): slow-cycling subpopulations of tumor cells that exhibit reversible sensitivity to therapy. These cells confer multi-drug tolerance, to targeted and chemotherapies alike, until the residual disease can establish a stable, drug-resistant state. The DTP state can exploit a multitude of distinct, yet interlaced, mechanisms to survive otherwise lethal drug exposures. Here, we categorize these multi-faceted defense mechanisms into unique Hallmarks of Cancer Drug Tolerance. At the highest level, these are comprised of heterogeneity, signaling plasticity, differentiation, proliferation/metabolism, stress management, genomic integrity, crosstalk with the tumor microenvironment, immune escape, and epigenetic regulatory mechanisms. Of these, epigenetics was both one of the first proposed means of non-genetic resistance and one of the first discovered. As we describe in this review, epigenetic regulatory factors are involved in most facets of DTP biology, positioning this hallmark as an overarching mediator of drug tolerance and a potential avenue to novel therapies.Copyright © 2023 Elsevier Inc. All rights reserved.