Systemic therapy options for urothelial carcinoma have expanded in recent years, with both immunotherapy and cytotoxic chemotherapy being widely available. However, we lack biomarkers to select which drug is likely to work best in individual patients. A new article in this journal by Jin, Xu, Su, et al reports that disruptive versus non‐disruptive TP53 mutations may guide these personalised therapy choices. Intriguingly, patients with disruptive TP53 tumour mutations had poor overall survival versus those with non‐disruptive TP53 mutations or wild type TP53 but responded particularly well to immunotherapy. Of relevance, an increased tumour mutational burden and increased effector CD8⁺ T‐cell infiltration was seen in tumours with disruptive mutations. The impact of different TP53 mutations on prognosis and therapy choices appears to be tumour‐ and therapy‐type specific, with no clear consensus on overall tumour phenotype according to type of mutation. Nonetheless, profiling of specific types of TP53 mutation is increasingly clinically feasible with targeted sequencing or immunohistochemistry. There is an urgent need for additional studies in urothelial cancer clarifying how the type of TP53 mutation present within a tumour can best be used as a predictive biomarker. Further important remaining questions include the impact of TP53 mutations on other clinically important aspects of the tumour microenvironment, including cancer‐associated fibroblasts. Furthermore, the impact of gain‐of‐function mutations in TP53 and other related genes signalling upstream or downstream of TP53 is of wide interest. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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