TP53肿瘤抑制基因的突变在癌症中非常常见，而试图恢复p53在肿瘤中的功能作为治疗策略已经开始了数十年。然而，这些药物开发计划中很少有人达到了临床试验的后期阶段，到目前为止在美国或欧洲还没有基于p53的治疗药物获批。这可能是因为作为核转录因子，p53不具备典型的药物靶标特征，因此长期被认为是难于药物开发的。尽管如此，近年来涌现了几种有前途的基于p53的治疗方法，包括改进早期策略的改进版本和使难以药物化的靶点药物化的新方法。能够保护p53免受其负调节因子的小分子或恢复突变p53蛋白功能的药物正受到越来越多的关注，并且定制特定类型的p53突变体的药物正在出现。与此同时，基因治疗策略和基于p53的免疫治疗方法也再次引起了关注。然而，仍然存在一些重大问题需要解决。本评述重新评估了针对p53功能失调癌症的治疗努力，并讨论了临床开发中遇到的挑战。© 2022. Springer Nature Limited.

Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development.© 2022. Springer Nature Limited.