p53, which is encoded by the most frequently mutated gene in cancer, TP53, is an attractive target for novel cancer therapies. Despite major challenges associated with this approach, several compounds that either augment the activity of wild-type p53 or restore all, or some, of the wild-type functions to p53 mutants are currently being explored. In wild-type TP53 cancer cells, p53 function is often abrogated by overexpression of the negative regulator MDM2, and agents that disrupt p53–MDM2 binding can trigger a robust p53 response, albeit potentially with induction of p53 activity in non-malignant cells. In TP53-mutant cancer cells, compounds that promote the refolding of missense mutant p53 or the translational readthrough of nonsense mutant TP53 might elicit potent cell death. Some of these compounds have been, or are being, tested in clinical trials involving patients with various types of cancer. Nonetheless, no p53-targeting drug has so far been approved for clinical use. Advances in our understanding of p53 biology provide some clues as to the underlying reasons for the variable clinical activity of p53-restoring therapies seen thus far. In this Review, we discuss the intricate interactions between p53 and its cellular and microenvironmental contexts and factors that can influence p53’s activity. We also propose several strategies for improving the clinical efficacy of these agents through the complex perspective of p53 functionality.

p53 由癌症中最常见的突变基因 TP53 编码，是新型癌症疗法的一个有吸引力的靶点。尽管这种方法面临重大挑战，但目前正在探索几种增强野生型 p53 活性或恢复 p53 突变体全部或部分野生型功能的化合物。在野生型 TP53 癌细胞中，p53 功能通常会因负调节因子 MDM2 的过度表达而被消除，而破坏 p53-MDM2 结合的药物可以触发强大的 p53 反应，尽管可能会在非恶性细胞中诱导 p53 活性。在 TP53 突变癌细胞中，促进错义突变体 p53 重折叠或无义突变体 TP53 翻译通读的化合物可能会引发有效的细胞死亡。其中一些化合物已经或正在对患有各种癌症的患者进行临床试验。尽管如此，迄今为止还没有p53靶向药物被批准用于临床。我们对 p53 生物学理解的进展为迄今为止发现的 p53 恢复疗法临床活性变化的根本原因提供了一些线索。在这篇综述中，我们讨论了 p53 与其细胞和微环境背景以及可能影响 p53 活性的因素之间复杂的相互作用。我们还提出了几种通过 p53 功能的复杂视角来提高这些药物临床疗效的策略。