随着对肿瘤细胞和肿瘤免疫微环境关系的认知不断深化，基于免疫检查点阻断的免疫治疗在近年取得了重大突破，提高了临床疗效，延长了癌症患者的生存期。然而，免疫治疗的新生或获得性耐药性大大抵消了其疗效，导致总反应率为20%-40%。因此，对肿瘤微环境和抗肿瘤免疫的调节需要进一步深入的了解。泛素化介导的蛋白质降解在蛋白质稳定、活化和动态以及细胞稳态调节中起着至关重要的作用。失调的泛素化和脱泛素化与生理和病理过程的变化密切相关，随后导致各种疾病，包括癌症。在本综述中，作者首先总结了泛素-蛋白酶体系统在肿瘤发展中的作用，以泛素共轭调节的p53、磷酸酰胺酶和张力均衡相似物以及Myc蛋白为例，然后分析了泛素化介导的免疫检查点在肿瘤微环境和免疫反应中的潜在意义，最后讨论了通过治疗靶向泛素-蛋白酶体途径对免疫治疗的影响，并旨在深入探讨更精准、更有效的癌症联合治疗策略。 © 2023 American Cancer Society.

With the continuous cognition of the relationship between tumor cells and tumor immune microenvironment, immunotherapy based on the immune checkpoint blockade has achieved great breakthroughs, led to improved clinical outcomes, and prolonged survival for cancer patients in recent years. Nevertheless, the de novo or acquired resistance to immunotherapy has greatly counteracted the efficacy, leading to a 20%-40% overall response rate. Thus, further in-depth understanding of the regulation of the tumor microenvironment and antitumor immunity is urgently warranted. Ubiquitination-mediated protein degradation plays vital roles in protein stabilization, activation, and dynamics as well as in cellular homeostasis modulation. The dysregulated ubiquitination and deubiquitination are closely related to the changes in physiological and pathological processes, which subsequently result in a variety of diseases including cancer. In this review, the authors first summarize the current knowledge about the involvement of the ubiquitin-proteasome system in tumor development with the ubiquitin conjugation-regulated stability of p53, phosphatase and tensin homolog, and Myc protein as examples, then dissect the potential implications of ubiquitination-mediated immune checkpoints degradation in tumor microenvironment and immune responses, and finally discuss the effects of therapeutically targeting the ubiquitin-proteasome pathway on immunotherapy, with the goal of providing deep insights into the exploitation of more precise and effective combinational therapy against cancer.© 2023 American Cancer Society.