It is well established that multifactorial drug resistance hinders successful cancer treatment. Tumor cell interactions with the tumor microenvironment (TME) are crucial in epithelial-mesenchymal transition (EMT) and multidrug resistance (MDR). TME-induced factors secreted by cancer cells and cancer-associated fibroblasts (CAFs) create an inflammatory microenvironment by recruiting immune cells. CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) and inflammatory tumor associated macrophages (TAMs) are main immune cell types which further enhance chronic inflammation. Chronic inflammation nurtures tumor-initiating/cancer stem-like cells (CSCs), induces both EMT and MDR leading to tumor relapses. Pro-thrombotic microenvironment created by inflammatory cytokines and chemokines from TAMs, MDSCs and CAFs is also involved in EMT and MDR. MDSCs are the most common mediators of immunosuppression and are also involved in resistance to targeted therapies, e.g. BRAF inhibitors and oncolytic viruses-based therapies. Expansion of both cancer and stroma cells causes hypoxia by hypoxia-inducible transcription factors (e.g. HIF-1α) resulting in drug resistance. TME factors induce the expression of transcriptional EMT factors, MDR and metabolic adaptation of cancer cells. Promoters of several ATP-binding cassette (ABC) transporter genes contain binding sites for canonical EMT transcription factors, e.g. ZEB, TWIST and SNAIL. Changes in glycolysis, oxidative phosphorylation and autophagy during EMT also promote MDR. Conclusively, EMT signaling simultaneously increases MDR.

Owing to the multifactorial nature of MDR, targeting one mechanism seems to be non-sufficient to overcome resistance. Targeting inflammatory processes by immune modulatory compounds such as mTOR inhibitors, demethylating agents, low-dosed histone deacetylase inhibitors may decrease MDR. Targeting EMT and metabolic adaptation by small molecular inhibitors might also reverse MDR. In this review, we summarize evidence for TME components as causative factors of EMT and anticancer drug resistance.

众所周知，多因素耐药性阻碍了成功的癌症治疗。肿瘤细胞与肿瘤微环境 (TME) 的相互作用在上皮间质转化 (EMT) 和多药耐药 (MDR) 中至关重要。癌细胞和癌症相关成纤维细胞 (CAF) 分泌的 TME 诱导因子通过募集免疫细胞产生炎症微环境。CD11b+/Gr-1+ 髓源性抑制细胞 (MDSC) 和炎性肿瘤相关巨噬细胞 (TAM) 是主要的免疫细胞类型，可进一步增强慢性炎症。慢性炎症会培育肿瘤起始/癌症干细胞样细胞 (CSC)，诱导 EMT 和 MDR，导致肿瘤复发。由来自 TAM、MDSC 和 CAF 的炎性细胞因子和趋化因子产生的促血栓形成微环境也参与 EMT 和 MDR。例如BRAF 抑制剂和基于溶瘤病毒的疗法。癌细胞和基质细胞的扩增通过缺氧诱导转录因子（例如HIF-1α）引起缺氧，从而导致耐药性。TME 因子诱导转录 EMT 因子的表达、MDR 和癌细胞的代谢适应。几个 ATP 结合盒 (ABC) 转运蛋白基因的启动子包含经典 EMT 转录因子的结合位点，例如ZEB、TWIST 和 SNAIL。EMT 期间糖酵解、氧化磷酸化和自噬的变化也会促进 MDR。最后，EMT 信号同时增加了 MDR。

由于 MDR 的多因素性质，针对一种机制似乎不足以克服耐药性。通过免疫调节化合物（例如 mTOR 抑制剂、去甲基化剂、低剂量组蛋白去乙酰化酶抑制剂）靶向炎症过程可能会降低 MDR。通过小分子抑制剂靶向 EMT 和代谢适应也可能逆转 MDR。在这篇综述中，我们总结了 TME 成分作为 EMT 和抗癌药物耐药性致病因素的证据。