TP53 mutation-biased CD8⁺ T cell exhaustion drives lethal outcome and therapy resistance in urothelial carcinoma

Emerging evidence has underscored non-cell-autonomous roles of mutant p53 in reshaping the composition and functional state of tumour immune microenvironment (TIME). However, the impact of p53 status on the clinical relevance and functional differentiation of CD8⁺ T cells remains poorly understood in urothelial carcinoma (UC).

Our study included 297 UC patients from two in-house cohorts and 871 UC patients from four public datasets to evaluate the impact of p53 status on the clinical implications of CD8⁺ T cells. Single-cell RNA sequencing, flow cytometry, immunohistochemistry, and bioinformatics analyses were performed to elucidate the role of p53 status in regulating CD8⁺ T cell polarisation and reshaping the TIME.

High CD8⁺ T cell infiltration correlated with favourable prognosis and improved survival following chemotherapy and PD-(L)1 blockade exclusively in p53-WT UC, while its association with prognosis and therapeutic benefit was abrogated in p53-mutant UC. Moreover, p53-mutant UC exhibited predominant infiltration of TIM3⁺ exhausted CD8⁺ T cells, accompanied by increased Treg and M2 macrophage infiltration.

The clinical significance and functional polarisation of CD8⁺ T cells in UC varied in a context-dependent manner according to p53 status. These findings provide novel insights to refine patient stratification and optimise personalised therapeutic strategies.