肿瘤的发展依赖于一个复杂和异常的组织环境，癌细胞在其中获取生长所需的营养物质，通过免疫逃逸生存，并获得介导侵袭和转移的间充质特性。肿瘤微环境中的基质细胞和可溶性介质表现出特征性的抗炎和促肿瘤活动。泛素化是一种至关重要的可逆转录后修饰，通过一个酶促级联反应在调节被修饰蛋白的稳定性、活性和定位方面发挥重要作用。积累的证据表明，一系列E3配体酶和脱泛素酶(DUB)精细地定位于多个信号通路、转录因子和关键酶上，以控制TME的几乎所有组分的功能。本综述系统地总结了与TME形成有关的关键底物蛋白以及主要识别这些蛋白的E3配体酶和DUB。此外，还介绍了几种有前途的技术，通过利用细胞内的E3泛素连接酶机制来实现有针对性的蛋白质降解。©2023作者

Tumor development relies on a complex and aberrant tissue environment in which cancer cells receive the necessary nutrients for growth, survive through immune escape, and acquire mesenchymal properties that mediate invasion and metastasis. Stromal cells and soluble mediators in the tumor microenvironment (TME) exhibit characteristic anti-inflammatory and protumorigenic activities. Ubiquitination, which is an essential and reversible posttranscriptional modification, plays a vital role in modulating the stability, activity and localization of modified proteins through an enzymatic cascade. This review was motivated by accumulating evidence that a series of E3 ligases and deubiquitinases (DUBs) finely target multiple signaling pathways, transcription factors and key enzymes to govern the functions of almost all components of the TME. In this review, we systematically summarize the key substrate proteins involved in the formation of the TME and the E3 ligases and DUBs that recognize these proteins. In addition, several promising techniques for targeted protein degradation by hijacking the intracellular E3 ubiquitin-ligase machinery are introduced.© 2023. The Author(s).