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.
Wen et al. (Sun,) studied this question.
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