靶向突变型p53的肿瘤治疗策略研究进展

Research Progress on Targeted Therapeutic Strategies for Mutant p53 in Cancer

摘要: p53是人类恶性肿瘤中突变频率最高的抑癌基因，其功能状态直接影响肿瘤的发生发展、治疗应答及患者预后。在正常生理状态下，p53作为基因组稳定性的关键调控者，通过诱导细胞周期阻滞、细胞凋亡及DNA修复等机制发挥核心抑癌功能。然而，TP53基因突变不仅导致其经典功能丧失，更赋予突变蛋白新的致癌活性，从而驱动肿瘤的侵袭转移、代谢重编程、治疗耐药及免疫微环境重塑等恶性进程。本综述系统阐述了p53蛋白的结构基础与核心生物学功能，重点剖析了突变型p53获得性致癌功能的分子机制。在此基础上，聚焦于直接靶向突变型p53的前沿治疗策略：基于蛋白降解靶向嵌合体等新技术的突变体清除策略、通过构象校正恢复野生型功能的再激活剂研发，以及特异性干预其异常致癌蛋白互作网络的创新方法。这些策略体现了从传统功能抑制到靶向干预的转变，为克服p53突变相关临床治疗困境提供了新的方向，对该领域的深入探索与未来发展具有重要的参考价值。

Abstract: p53 is the most frequently mutated tumor suppressor gene in human malignancies, whose functional status directly influences tumor initiation, progression, therapeutic response, and patient prognosis. Under normal physiological conditions, p53 acts as a critical regulator of genome stability, exerting its core tumor-suppressive functions through mechanisms including cell cycle arrest, apoptosis induction, and DNA repair. However, mutations in the TP53 gene not only lead to the loss of these classical functions but often confer oncogenic activities to the mutant protein, thereby driving malignant processes such as tumor invasion and metastasis, metabolic reprogramming, therapy resistance, and immune microenvironment remodeling. This review systematically elaborates on the structural basis and core biological functions of the p53 protein, with a focused analysis of the molecular mechanisms underlying the gain-of-function oncogenic properties of mutant p53. Furthermore, it concentrates on advanced therapeutic strategies directly targeting mutant p53: mutation clearance strategies based on novel technologies such as proteolysis-targeting chimeras, the development of reactivators that restore wild-type function through conformational correction, and innovative methods to specifically disrupt its aberrant oncogenic protein interaction networks. These strategies represent a shift from traditional functional inhibition to precise targeted intervention, offering new directions for addressing the clinical challenges associated with p53 mutations. This work holds significant reference value for the continued exploration and future development of this research field.