Abstract
TP53 is frequently mutated in bladder cancer and is associated with aggressive disease, yet actionable strategies that also improve responses to immune checkpoint blockade remain limited. Here we show that APR-246 (eprenetapopt), a mutant p53–reactivating agent, preferentially reduces viability in TP53-mutant bladder cancer cell lines and that its activity appears to be partially dependent on mutant p53. Mechanistically, APR-246 induces pronounced reactive oxygen species accumulation and engages ferroptosis and apoptosis in parallel, accompanied by reactivation of p53-associated transcriptional programmes. RNA sequencing and orthogonal validation further reveal increased expression and secretion of the T cell–recruiting chemokines CCL5 and CXCL10. In syngeneic subcutaneous and orthotopic bladder tumour models, APR-246 suppresses tumour growth and is associated with increased infiltration of CD8⁺ and CD4⁺ T cells and natural killer cells, though limited by sample size in animal models; This antitumour effect is attenuated in immunodeficient hosts. Notably, APR-246 augments the efficacy of anti–PD-1 therapy and further enriches effector immune infiltration. Together, these findings link mutant p53 targeting and redox-driven cell death to immune remodelling, providing a mechanistic rationale for combining APR-246 with PD-1 blockade in bladder cancer.
Data availability
The data supporting the findings of this study are available within the article. RNA-seq data have been deposited in GEO (GSE308506, www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE308506). All data will be made available on reasonable request.
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Acknowledgements
We thank Figuredraw for technical support. We also thank MedChemExpress (MCE) for providing chemical reagents used in this study. This work was supported by the National Natural Science Foundation of China under Grant 82403585.
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This work was supported by the National Natural Science Foundation of China under Grant 82403585.
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Conceptualization, Z.C.; methodology, Z.C. and S.C.; software, S.C. and Y.D.; validation, Z.C., S.C., G.Z. and Y.H.; formal analysis, Z.C., G.Z. and Y.D.; investigation, Z.C., S.C., G.Z. and Y.D.; resources, H.L., X.M., X.Z., Z.L. and Y.H.; data curation, Z.C.; writing—original draft preparation, Z.C., S.C., G.Z., Y.D. and H.L.; writing—review and editing, Z.L. and Y.H.; visualization, Z.C. and S.C.; supervision, H.L., X.M., X.Z., Z.L. and Y.H.; project administration, X.M., X.Z. and Y.H.; funding acquisition, H.L., X.M., X.Z., Z.L. and Y.H.All authors have read and agreed to the published version of the manuscript.
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Zhang, C., Cao, S., Zeng, G. et al. APR-246 drives ROS-dependent ferroptosis and apoptosis and enhances anti–PD-1 efficacy in bladder cancer. Sci Rep (2026). https://doi.org/10.1038/s41598-026-44653-8
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DOI: https://doi.org/10.1038/s41598-026-44653-8
