肝细胞癌（HCC）是一种异质性和侵袭性的肝癌，治疗选择有限。索拉非尼虽然是晚期HCC的标准疗法，但经常遭遇抗药性，强调了揭示其潜在机制并开发有效治疗方法的必要性。本综述突出了肿瘤微环境、癌干细胞（CSCs）和上皮间质转化（EMT）在索拉非尼抗药性背景下的关键相互作用。肿瘤微环境涵盖缺氧、免疫细胞、基质细胞和外泌体等因素，对HCC进展和治疗反应产生重要影响。缺氧条件和免疫细胞浸润形成免疫抑制环境，保护肿瘤细胞免受免疫监视，并阻碍治疗效果。此外，存在CSCs被认为是索拉非尼抗药性的突出因素，CD133+ CSCs与药物抗性和肿瘤发生有关。此外，CSCs经历EMT过程，与肿瘤进展、CSC激活以及进一步促进索拉非尼抗药性、转移和肿瘤诱导能力紧密相关。阐明肿瘤微环境、CSCs和索拉非尼抗药性之间的关系对于发展可靠的预测治疗反应的生物标志物具有至关重要的意义。新的治疗策略必须考虑肿瘤微环境和CSC激活的影响，以有效克服HCC中的索拉非尼抗药性。版权所有 © 2023 Chen，Du，Guan和Yan。

Hepatocellular carcinoma (HCC) is a heterogeneous and aggressive liver cancer that presents limited treatment options. Despite being the standard therapy for advanced HCC, sorafenib frequently encounters resistance, emphasizing the need to uncover the underlying mechanisms and develop effective treatments. This comprehensive review highlights the crucial interplay between the tumor microenvironment, cancer stem cells (CSCs), and epithelial-mesenchymal transition (EMT) in the context of sorafenib resistance. The tumor microenvironment, encompassing hypoxia, immune cells, stromal cells, and exosomes, exerts a significant impact on HCC progression and therapy response. Hypoxic conditions and immune cell infiltration create an immunosuppressive milieu, shielding tumor cells from immune surveillance and hindering therapeutic efficacy. Additionally, the presence of CSCs emerges as a prominent contributor to sorafenib resistance, with CD133+ CSCs implicated in drug resistance and tumor initiation. Moreover, CSCs undergo EMT, a process intimately linked to tumor progression, CSC activation, and further promotion of sorafenib resistance, metastasis, and tumor-initiating capacity. Elucidating the correlation between the tumor microenvironment, CSCs, and sorafenib resistance holds paramount importance in the quest to develop reliable biomarkers capable of predicting therapeutic response. Novel therapeutic strategies must consider the influence of the tumor microenvironment and CSC activation to effectively overcome sorafenib resistance in HCC.Copyright © 2023 Chen, Du, Guan and Yan.