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<p>Overcoming profoundly suppressed programmed cell death and an immunosuppressive tumor microenvironment (TME) remains a formidable challenge in gemcitabine-cisplatin-resistant muscle-invasive bladder cancer (GP-R MIBC). To address this, we developed a glutathione (GSH)-responsive nanosystem for co-delivering the cathepsin H (CTSH) inhibitor prodrug E64d and a cisplatin prodrug Pt(IV), implementing a spatiotemporally coordinated “unlock-and-trigger” strategy. Mechanistically, the activated E64 irreversibly inhibits CTSH, thereby unlocking the TNFα–caspase-8 axis to reinstate GSDMD-mediated pyroptosis. Concurrently, caspase-8 dually activates caspase-3 via both direct cleavage and the Bid-mediated mitochondrial pathway. This primed state ensures that the DNA damage induced by the reduced Pt(IV) robustly triggers caspase-3/GSDME-mediated pyroptosis. This synergistic dual-pyroptosis pathway potently stimulates immunogenic cell death (ICD) and reverses the immunosuppressive TME by promoting dendritic cell maturation and CD8<sup>+</sup>T lymphocyte infiltration. Consequently, when combined with an αPD-L1 antibody, this strategy effectively eradicated GP-R bladder tumors and suppressed recurrence in vivo, demonstrating compelling translational potential. In summary, our work presents a translatable nanotherapeutic strategy that resensitizes GP-R MIBC to chemo-immunotherapy by leveraging a synergistic “unlock-and-trigger” mechanism to reactivate pyroptosis.</p> Graphical abstract <p></p>

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Unlocking caspase-8 enables Pt(IV) to trigger robust caspase-3/GSDME-mediated pyroptosis via drug co-delivery in chemoresistant bladder cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月12日

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  • Jintao Wen,
  • Baotong Zhou,
  • Hanchen Zhang,
  • Yongbo Tang,
  • Haiwei Hu,
  • Haihua Xiao,
  • Bo Ge

摘要

Overcoming profoundly suppressed programmed cell death and an immunosuppressive tumor microenvironment (TME) remains a formidable challenge in gemcitabine-cisplatin-resistant muscle-invasive bladder cancer (GP-R MIBC). To address this, we developed a glutathione (GSH)-responsive nanosystem for co-delivering the cathepsin H (CTSH) inhibitor prodrug E64d and a cisplatin prodrug Pt(IV), implementing a spatiotemporally coordinated “unlock-and-trigger” strategy. Mechanistically, the activated E64 irreversibly inhibits CTSH, thereby unlocking the TNFα–caspase-8 axis to reinstate GSDMD-mediated pyroptosis. Concurrently, caspase-8 dually activates caspase-3 via both direct cleavage and the Bid-mediated mitochondrial pathway. This primed state ensures that the DNA damage induced by the reduced Pt(IV) robustly triggers caspase-3/GSDME-mediated pyroptosis. This synergistic dual-pyroptosis pathway potently stimulates immunogenic cell death (ICD) and reverses the immunosuppressive TME by promoting dendritic cell maturation and CD8+T lymphocyte infiltration. Consequently, when combined with an αPD-L1 antibody, this strategy effectively eradicated GP-R bladder tumors and suppressed recurrence in vivo, demonstrating compelling translational potential. In summary, our work presents a translatable nanotherapeutic strategy that resensitizes GP-R MIBC to chemo-immunotherapy by leveraging a synergistic “unlock-and-trigger” mechanism to reactivate pyroptosis.

Graphical abstract