Calcium sulfide based nanoreservoirs elicit dual pyroptosis pathways for enhanced anti-tumor immunity

The therapeutic efficacy of immunotherapy for most solid tumors is unsatisfactory due to the "immune-cold" nature. As a form of lytic pro-inflammatory programmed cell death, pyroptosis can release abundant immunogenic damage-associated molecular patterns to extracellular milieu, exhibiting self-cascade amplifying capacity for cancer immunotherapy. However, the activation of the caspase-3-mediated pyroptosis is difficult because mRNA hypermethylation induces the down-regulated GSDME expression. Herein, an integrated strategy to elicit dual pyroptosis pathways is introduced based on calcium sulfide-based nanoreservoirs (denoted as CSSG). CSSG are degraded in the aggravated acidic tumor microenvironment (TME) triggered by the surface GOx participating oxidation and result in the avalanching generation of H2S and Ca2+, which elevate oxidative pressure and induce mitochondrial respiration inhibition. Moreover, the sudden surge in H2S evokes GSDMD mediated pyroptosis through "DUSP6/ERK/NLRP3/caspase-1" signaling pathway, which synergistically reinforces the performance of the Ca2+ overloading initiating GSDME-mediated pyroptosis. CSSG elicit robust pyroptotic cell death to effectively stimulate tumor immunogenicity, and promote an impressive antitumor immunity with effective elimination of primary and distant tumors. Collectively, this work establishes TME-associated degradable nanomaterials to introduce dual pyroptosis pathways simultaneously and has a promising prospect in optimizing cancer immunotherapy.