Multifunctional self-cascade nanoplatform for efficient immunotherapy through synergizing pyroptosis and self-augmented activation of cGAS-STING pathway.

Immunotherapy is a promising treatment strategy for tumors; however, its efficacy is limited by the complicated immunosuppressive tumor microenvironment (TME). Herein, we developed a simple drug-free bioactive multifunctional nanoplatform (named MnO2-CaS) that was sustainably degraded in a weakly acidic TME to release calcium ions (Ca2+) and generate manganese ions (Mn2+) and hydrogen sulfide (H2S). Mn2+ activated and amplified the cyclic GMP-AMP (cGAMP) synthase stimulator of interferon gene (cGAS-STING) pathway and simultaneously produced oxygen to alleviate hypoxia. H2S, a therapeutic gas, not only induced mitochondrial damage but also prevented the extracellular efflux of Ca2+, leading to a sharp increase in Ca2+ concentration in mitochondria. The abnormal intracellular Ca2+ overload induced pyroptosis, disturbed mitochondrial respiration, and reduced metabolic oxygen consumption, thereby alleviating hypoxia and amplifying oxidative stress. Gasdermin-mediated pyroptosis facilitated mitochondrial DNA (mtDNA) release, further amplifying cGAS-STING pathway activation to induce robust antitumor immunity. In addition, the nanoplatform generated abundant reactive oxygen species (ROS) and depleted glutathione (GSH), inhibiting glutathione peroxidase 4 (GPX4) biosynthesis. This process exacerbated lipid peroxidation and induced ferroptosis. Altogether, the self-cascading immunomodulatory nanoplatform alleviated tumor hypoxia to mitigate immunosuppression and amplify pyroptosis-driven cGAS-STING pathway activation. The nanoplatform synergized with chemodynamic therapy (CDT) and ferroptosis to effectively suppress the growth and metastasis of both primary and distant tumors. This study provides a novel strategy for co-activating pyroptosis and cGAS-STING signaling in immunotherapy, offering insights for developing safe and effective immunotherapies for cancer treatment.