传统的肿瘤化疗常常受到药物耐受性的严重阻碍。表观遗传学改变以及其他机制，如药物外排、药物代谢和生存通路的参与，在逃避药物压力方面至关重要。越来越多的证据表明，肿瘤细胞的一个亚群体通常能够通过进入“持久存在”状态，并且细胞增殖最小程度地忍受药物攻击。这些持久存在细胞的分子特征正逐渐被揭示出来。尤其需要注意的是，“持久存在细胞”作为一种细胞储存库，最终可以在停药压力后重新填充肿瘤，并且参与到获取稳定的药物抗性特征中。这突显了容忍性细胞的临床意义。越来越多的证据强调，调节表观遗传组学是逃避药物压力的必要策略。染色质重塑、DNA甲基化改变以及非编码RNA表达和功能的失调对这种持久存在状态产生了重大影响。不难理解，针对适应性表观遗传改变的靶向治疗越来越被认为是恢复药物敏感性的合适治疗策略。此外，还探索了改变肿瘤微环境和“停药期”的方法来操纵表观遗传组学。但是，适应性策略的异质性以及缺乏针对性治疗显著阻碍了表观遗传治疗转化为实际应用于临床的进展。在本综述中，我们全面分析了药物耐受细胞适应的表观遗传学改变、截至目前采用的治疗策略，以及它们的限制和未来发展前景。

Traditional chemotherapy against cancer is often severely hampered by acquired resistance to the drug. Epigenetic alterations and other mechanisms like drug efflux, drug metabolism, and engagement of survival pathways are crucial in evading drug pressure. Herein, growing evidence suggests that a subpopulation of tumor cells can often tolerate drug onslaught by entering a "persister" state with minimal proliferation. The molecular features of these persister cells are gradually unraveling. Notably, the "persisters" act as a cache of cells that can eventually re-populate the tumor post-withdrawal drug pressure and contribute to acquiring stable drug-resistant features. This underlines the clinical significance of the tolerant cells. Accumulating evidence highlights the importance of modulation of the epigenome as a critical adaptive strategy for evading drug pressure. Chromatin remodeling, altered DNA methylation, and de-regulation of non-coding RNA expression and function contribute significantly to this persister state. No wonder targeting adaptive epigenetic modifications is increasingly recognized as an appropriate therapeutic strategy to sensitize them and restore drug sensitivity. Furthermore, manipulating the tumor microenvironment and "drug holiday" is also explored to maneuver the epigenome. However, heterogeneity in adaptive strategies and lack of targeted therapies have significantly hindered the translation of epigenetic therapy to the clinics. In this review, we comprehensively analyze the epigenetic alterations adapted by the drug-tolerant cells, the therapeutic strategies employed to date, and their limitations and future prospects.Copyright © 2023 Elsevier Inc. All rights reserved.