Lipids, phospholipids and cholesterol in particular, are the predominant components of the plasma membrane, wherein multidrug efflux transporters of the ATP-binding cassette (ABC) superfamily reside as integral pump proteins. In the current review, we discuss how lipids potently modulate the expression and activity of these multidrug efflux pumps, contributing to the development of the multidrug resistance (MDR) phenotype in cancer. The molecular mechanisms underlying this modulation of the MDR phenotype are pleiotropic. First, notwithstanding the high intra-and inter-tumor variability, MDR cells display an altered composition of plasma membrane phospholipids and glycosphingolipids, and are enriched with very long saturated fatty acid chains. This feature, along with the increased levels of cholesterol, decrease membrane fluidity, alter the spatial organization of membrane nano- and micro-domains, interact with transmembrane helices of ABC transporters, hence favoring drug binding and release. Second, MDR cells exhibit a peculiar membrane lipid composition of intracellular organelles including mitochondria and endoplasmic reticulum (ER). In this respect, they contain a lower amount of oxidizable fatty acids, hence being more resistant to oxidative stress and chemotherapy-induced apoptosis. Third, drug resistant cancer cells have a higher ratio of monosatured/polyunsatured fatty acids: this lipid signature reduces the production of reactive aldehydes with cytotoxic and pro-inflammatory activity and, together with the increased activity of anti-oxidant enzymes, limits the cellular damage induced by lipid peroxidation. Finally, specific precursors of phospholipids and cholesterol including ceramides and isoprenoids, are highly produced in MDR cells; by acting as second messengers, they trigger multiple signaling cascades that induce the transcription of drug efflux transporter genes and/or promote a metabolic reprogramming which supports the MDR phenotype.

High-throughput lipidomics and computational biology technologies are a great tool in analyzing the tumor lipid signature in a personalized manner and in identifying novel biomarkers of drug resistance. Moreover, beyond the induction of MDR, lipid metabolism offers a remarkable opportunity to reverse MDR by using lipid analogues and repurposing lipid-targeting drugs (e.g. statins and aminobisphosphonates) that reprogram the lipid composition of drug resistant cells, hence rendering them drug sensitive.

脂质，磷脂和胆固醇尤其是质膜的主要成分，其中ATP结合盒（ABC）超家族的多药外排转运蛋白作为整体泵蛋白存在。在当前的审查中，我们讨论脂质如何有效地调节这些多药外排泵的表达和活性，从而促进癌症中多药耐药性（MDR）表型的发展。MDR表型调节的分子机制是多效性的。首先，尽管肿瘤内和肿瘤间的高变异性，MDR细胞仍显示出质膜磷脂和糖鞘脂的组成发生变化，并富含非常长的饱和脂肪酸链。此功能以及胆固醇水平的提高会降低膜的流动性，改变膜纳米域和微域的空间组织，与ABC转运蛋白的跨膜螺旋相互作用，因此有利于药物结合和释放。其次，MDR细胞显示出细胞内细胞器的特殊膜脂质成分，包括线粒体和内质网（ER）。在这方面，它们包含较少量的可氧化脂肪酸，因此对氧化应激和化学疗法诱导的细胞凋亡具有更强的抵抗力。第三，耐药癌细胞具有更高比例的单/多不饱和脂肪酸：这种脂质特征减少了具有细胞毒性和促炎活性的反应性醛的产生，并与增加的抗氧化酶活性一起，限制了细胞损伤由脂质过氧化作用诱导。最后，在MDR细胞中大量产生磷脂和胆固醇的特定前体，包括神经酰胺和类异戊二烯。通过充当第二信使，它们触发了多个信号级联反应，这些信号级联反应诱导药物外排转运蛋白基因的转录和/或促进支持MDR表型的代谢重编程。

高通量脂质组学和计算生物学技术是一种以个性化方式分析肿瘤脂质特征并鉴定耐药性新生物标志物的绝佳工具。此外，除了诱导MDR以外，脂质代谢还提供了绝佳的机会来逆转MDR，方法是使用脂质类似物并重新利用靶向脂质的药物（例如他汀类药物和氨基双膦酸盐）来重新编程耐药细胞的脂质组成，从而使其对药物敏感。