E3 泛素连接酶 (E3s) 在调节蛋白质泛素化的特异性方面发挥着关键作用，其作为肿瘤免疫反应调节剂的重要功能引起了人们的极大兴趣。 RBCK1（一种 RBR E3 连接酶）参与免疫调节和肿瘤发展。然而，RBCK1 对神经胶质瘤的潜在影响仍然是个谜。在本研究中，我们对多层次数据进行了综合分析，揭示了RBCK1在泛癌，特别是胶质瘤中的分布特征。使用免疫组织化学、细胞生物学测定和异种移植实验进一步证实了 RBCK1 的功能作用。研究发现，多种类型癌症中 RBCK1 的异常上升可通过调节免疫调节剂、癌症免疫周期和免疫细胞浸润来重塑神经胶质瘤的免疫抑制微环境。值得注意的是，MES-like/RBCK1High 细胞群是微环境中独特的细胞亚群，可抑制胶质瘤中 T 细胞介导的细胞杀伤。 RBCK1 表达水平升高表明神经胶质瘤亚型的特征是免疫抑制和对免疫治疗反应低下，但对抗血管生成治疗的反应却出人意料地增加。总之，抗 RBCK1 靶向治疗可能有益于神经胶质瘤的治疗。此外，RBCK1 有助于预测神经胶质瘤的分子亚型和患者对不同临床治疗的反应率，这可以指导个性化治疗。© 2023 作者。

E3 ubiquitin ligases (E3s) play a pivotal role in regulating the specificity of protein ubiquitination, and their significant functions as regulators of immune responses against tumors are attracting considerable interest. RBCK1-an RBR E3 ligase-is involved in immune regulation and tumor development. However, the potential effect of RBCK1 on glioma remains enigmatic. In the present study, we performed comprehensive analyses of multilevel data, which disclosed distribution characteristics of RBCK1 in pan-cancer, especially in glioma. Functional roles of RBCK1 were further confirmed using immunohistochemistry, cell biological assays, and xenograft experiments. Aberrant ascending of RBCK1 in multiple types of cancer was found to remodel the immunosuppressive microenvironment of glioma by regulating immunomodulators, cancer immunity cycles, and immune cell infiltration. Notably, the MES-like/RBCK1High cell population, a unique subset of cells in the microenvironment, suppressed T cell-mediated cell killing in glioma. Elevated expression levels of RBCK1 suggested a glioma subtype characterized by immunosuppression and hypo-responsiveness to immunotherapy but manifesting surprisingly increased responses to anti-angiogenic therapy. In conclusion, anti-RBCK1 target therapy might be beneficial for glioma treatment. Moreover, RBCK1 assisted in predicting molecular subtypes of glioma and response rates of patients to different clinical treatments, which could guide personalized therapy.© 2023 The Authors.