Dynamic Redox‐Switchable Nanotransducer Enabling Spatiotemporal cGAS‐STING Remodeling and Immunogenic Cell Death Induction for Cancer Immunotherapy

Abstract Achieving targeted activation of the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway is a significant challenge for cancer immunotherapy. To address this issue, a reversible reactive oxygen species (ROS) generator/capture is prepared, defined as CZFT NPs, consisting of Zr/Fe dual‐doped hollow CeO ₂ (CZFO) nanozyme and hypoxia‐activated prodrug tirapazamine (TPZ). CZFT shows superoxide dismutase‐like activity in normal physiological environments and exhibits ROS scavenging ability, which can effectively enhance its biosafety. In acidic tumor microenvironment (TME), CZFT NPs display robust peroxidase‐like and glutathione peroxidase‐like activities. Moreover, the doping of Zr/Fe improves their sono‐carrier dynamics while giving them excellent magnetic resonance imaging (MRI) and computed tomography (CT) imaging capabilities. These processes significantly increase ROS generation within tumor cells and trigger mitochondrial damage to release endogenous mitochondrial DNA (mtDNA). Moreover, Fe ions improve the cGAS sensitivity to damaged DNA, thereby selectively activating the cGAS‐STING pathway of tumors. Furthermore, sonodynamic therapy augments the hypoxia level to activate TPZ for specific chemotherapy, facilitating cancer cell immunogenic cell death. This dual‐pronged strategy synergistically stimulates dendritic cell maturation, alleviates the immunosuppressive TME, and augments NK and CD8 ⁺ T cells driven immunotherapy, thereby inhibiting cancer proliferation and metastasis. In summary, CZFT NPs demonstrate a groundbreaking paradigm for overcoming critical challenges associated with conventional STING agonists.