Zeng Qinru, Zeng Shaocheng, Dai Xiaofeng, Ding Yun, Huang Chunye, Ruan Ruiwen, Xiong Jianping, Tang Xiaomei, Deng Jun
Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China.
Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi 330006, China.
Genes Dis. 2024 Mar 28;11(6):101279. doi: 10.1016/j.gendis.2024.101279. eCollection 2024 Nov.
Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%-40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.
小鼠双微体2（MDM2）通过p53依赖和p53非依赖信号通路在细胞周期、细胞凋亡、DNA修复及癌基因激活过程中发挥着重要作用。多项临床前研究表明，MDM2参与肿瘤免疫逃逸。因此，基于MDM2对肿瘤细胞内在免疫调节及免疫微环境的调控已引起越来越多的研究关注。近年来，靶向PD-1/PD-L1的免疫检查点抑制剂已在临床上广泛应用。然而，单药治疗的有效率仅约为20%-40%，这可能与癌蛋白失调导致的原发性和继发性耐药有关。在此，我们综述了MDM2在免疫治疗过程中调节免疫微环境、肿瘤免疫逃逸及超进展方面的作用。此外，我们总结了在MDM2过表达或扩增的肿瘤中使用MDM2抑制剂联合免疫治疗的临床前和临床研究结果。结果显示，抑制MDM2可能是增强免疫治疗效果的一种有前景的策略。
