尽管癌症治疗已经得到了发展，但大多数治疗方案的成功一直受到药物抵抗的限制。肿瘤细胞可塑性在癌症进展、癌症干性以及药物抵抗中的关键作用最近已经浮出水面。细胞可塑性推动肿瘤细胞可逆地转换它们的细胞特性，类似于分化和去分化，以适应药物治疗。这种表型开关由转录组的改变驱动。KLF和SOX家族的几个多能因子与癌症发病密切相关，并已被揭示出调节肿瘤细胞可塑性。在本综述中，我们特别总结了关于KLF4、KLF5和SOX因子在癌症发展和进化中的最新研究，重点关注它们在癌症起源、侵袭、肿瘤层次结构和异质性以及谱系可塑性中的作用。此外，我们还讨论了这些转录因子的各种调节以及相关的前沿药物开发方法，这些方法可以用于针对“难以治愈”的转录因子，如PROTAC和PPI靶向，以实现靶向癌症治疗。先进的知识可以为开发针对转录调控的新药物铺平道路，并可能改善癌症治疗的结果。Copyright © 2023 Elsevier Ltd. All rights reserved.

Despite the development of cancer therapies, the success of most treatments has been impeded by drug resistance. The crucial role of tumor cell plasticity has emerged recently in cancer progression, cancer stemness and eventually drug resistance. Cell plasticity drives tumor cells to reversibly convert their cell identity, analogous to differentiation and dedifferentiation, to adapt to drug treatment. This phenotypical switch is driven by alteration of the transcriptome. Several pluripotent factors from the KLF and SOX families are closely associated with cancer pathogenesis and have been revealed to regulate tumor cell plasticity. In this review, we particularly summarize recent studies about KLF4, KLF5 and SOX factors in cancer development and evolution, focusing on their roles in cancer initiation, invasion, tumor hierarchy and heterogeneity, and lineage plasticity. In addition, we discuss the various regulation of these transcription factors and related cutting-edge drug development approaches that could be used to drug "undruggable" transcription factors, such as PROTAC and PPI targeting, for targeted cancer therapy. Advanced knowledge could pave the way for the development of novel drugs that target transcriptional regulation and could improve the outcome of cancer therapy.Copyright © 2023 Elsevier Ltd. All rights reserved.