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 MnO 2 –CaS) that was sustainably degraded in a weakly acidic TME to release calcium ions (Ca 2+ ) and generate manganese ions (Mn 2+ ) and hydrogen sulfide (H 2 S). Mn 2+ activated and amplified the cyclic GMP-AMP (cGAMP) synthase stimulator of interferon gene (cGAS–STING) pathway and simultaneously produced oxygen to alleviate hypoxia. H 2 S, a therapeutic gas, not only induced mitochondrial damage but also prevented the extracellular efflux of Ca 2+ , leading to a sharp increase in Ca 2+ concentration in mitochondria. The abnormal intracellular Ca 2+ 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.