p53 was discovered 45 years ago as an SV40 large T antigen binding protein, coded by the most frequently mutated TP53 gene in human cancers. As a transcription factor, p53 is tightly regulated by a rich network of post-translational modifications to execute its diverse functions in tumor suppression. Although early studies established p53-mediated cell-cycle arrest, apoptosis, and senescence as the classic barriers in cancer development, a growing number of new functions of p53 have been discovered and the scope of p53-mediated anti-tumor activity is largely expanded. Here, we review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that contribute to tumor suppression. We also discuss the challenge regarding how to activate p53 function specifically effective in inhibiting tumor growth without harming normal homeostasis for cancer therapy.

p53 于 45 年前被发现，是一种 SV40 大 T 抗原结合蛋白，由人类癌症中突变最频繁的TP53基因编码。作为一种转录因子，p53 受到丰富的翻译后修饰网络的严格调控，以执行其在肿瘤抑制中的多种功能。尽管早期研究将p53介导的细胞周期停滞、细胞凋亡和衰老确定为癌症发展的经典障碍，但越来越多的p53新功能被发现，p53介导的抗肿瘤活性范围也大大扩展。在这里，我们回顾了 p53 调控不同层面的复杂性，以及 p53 通路在代谢、铁死亡、免疫和其他有助于肿瘤抑制的方面的最新进展。我们还讨论了如何激活 p53 功能以特别有效地抑制肿瘤生长而不损害癌症治疗的正常稳态的挑战。