TP53肿瘤抑制基因是人类患癌的最常见基因变异，并已成为肿瘤学研究的主要焦点。 p53蛋白是一种转录因子，能够激活多个靶基因的表达并在调节细胞周期、凋亡和基因组稳定性方面发挥关键作用，被广泛认为是“基因组守护者”。越来越多的证据表明，p53还调节细胞代谢、铁死亡、肿瘤微环境、自噬等，这些都有助于抑制肿瘤。 TP53突变不仅会损害其肿瘤抑制功能，还会赋予p53突变体致癌的特性。由于p53在大多数恶性肿瘤中突变和失活，因此它成为开发新型抗癌药物的非常有吸引力的目标。然而，直到最近，p53被认为是一种“无法药物化”的目标，针对p53的治疗方案的进展很少。在这里，我们系统地回顾了p53信号通路的多种分子机制以及TP53突变对肿瘤进展的影响。我们还讨论了p53蛋白的关键结构特征以及oncogenic突变所导致的失活。此外，我们还回顾了在针对p53的治疗方案方面所做的努力，以及在临床开发中遇到的挑战。©2023.作者。

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. The p53 protein is a transcription factor that can activate the expression of multiple target genes and plays critical roles in regulating cell cycle, apoptosis, and genomic stability, and is widely regarded as the "guardian of the genome". Accumulating evidence has shown that p53 also regulates cell metabolism, ferroptosis, tumor microenvironment, autophagy and so on, all of which contribute to tumor suppression. Mutations in TP53 not only impair its tumor suppressor function, but also confer oncogenic properties to p53 mutants. Since p53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs. However, until recently, p53 was considered an "undruggable" target and little progress has been made with p53-targeted therapies. Here, we provide a systematic review of the diverse molecular mechanisms of the p53 signaling pathway and how TP53 mutations impact tumor progression. We also discuss key structural features of the p53 protein and its inactivation by oncogenic mutations. In addition, we review the efforts that have been made in p53-targeted therapies, and discuss the challenges that have been encountered in clinical development.© 2023. The Author(s).