Reply to ‘Heterogeneity of TP53 mutations necessitates differentiation with p53-rescue therapies’

We thank Wu et al. for their comments on our Review (Peuget, S., Zhou, X. & Selivanova, G. Translating p53-based therapies for cancer into the clinic. Nat. Rev. Cancer 24, 192–215 (2024))¹; they raise some interesting points that we respond to below (Wu, J., Song, H., Xiao, S. & Lu, M. Heterogeneity of TP53 mutations necessitates differentiation with p53-rescue therapies. Nat. Rev. Cancer https://doi.org/10.1038/s41568-025-00826-7 (2025))².

Approximately half of all human cancers express mutants of the tumour suppressor p53, with loss of function owing to just a single amino acid residue substitution. These p53 mutants, often overexpressed, could be regarded as a loaded gun — but with a jammed trigger. As we outlined in our Review¹, this makes the idea of a cancer therapy strategy aimed at restoring wild-type p53 tumour-suppressor function to mutant p53 a very attractive goal. However, despite considerable research efforts, the field has yet to produce clinical advancements based on mutant p53 restoration.