癌细胞常常表现出对多种药物的内在或获得性耐药性，限制了治疗的成功。多药耐药的主要机制之一是过度表达介导药物外泄的ATP结合盒（ABC）转运体，其中ABCB1、ABCG2和ABCC1已知会导致癌症化疗耐药性。高分辨率结构、生物物理学和计算模拟研究已经在了解这些ABC转运体介导的药物转运机制方面取得了巨大的进展，同时利用辐射免疫和热疗以及纳米医学等几种有希望的疗法已被用于克服ABC转运体介导的癌症化疗耐药性。在这篇综述中，我们重点强调过去5年内在ABCB1、ABCG2和ABCC1等三种被认为具有临床重要性的转运体上取得的进展。我们讨论了从结构信息中获得的它们广泛底物特异性的分子基础，并讨论了阻断ABC转运体功能的新方法。此外，我们还简要讨论了CRISPR-Cas9对ABC转运体的遗传修饰以及通过重新设计氨基酸序列改变转运方向从而实现外泄到内泵的方法。我们建议将目前关于ABC转运体结构、机制和调控的信息应用于临床试验，以提高癌症患者的化疗药物效果。© 2023。这是美国政府的作品，在美国不受版权保护；外国可能适用版权保护。

Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. Furthermore, genetic modification of ABC transporters by CRISPR-Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.