Biodegradable Mn-LDH-Ce6 potentiates cGas-STING pathway activation through sonodynamic-propelled pyroptosis for synergistic tumor immunotherapy

While immunotherapy represents a breakthrough in cancer treatment by enabling specific tumor targeting with reduced toxicity, its success is often impeded by the immunosuppressive tumor microenvironment (TME). Conditions within the TME, particularly hypoxia and high glutathione (GSH) concentrations, actively suppress immune activation, leading to suboptimal therapeutic outcomes. To address these limitations, we developed a manganese-doped layered double hydroxide nanosystem loaded with chlorin e6 (Mn-LDH-Ce6). By catalyzing the decomposition of endogenous H 2 O 2 into oxygen, the platform’s catalase (CAT)-mimetic function enhances the sonodynamic therapy under ultrasound. This synergistically results in a pronounced increase in ROS and oxidative stress, while the subsequent irradiation further propagates ROS generation and directly initiates pyroptosis. However, the elevated glutathione levels in the TME paradoxically counteract this effect by scavenging oxidative species and exacerbating immunosuppression, ultimately compromising therapeutic outcomes. To disrupt this defense mechanism, Mn-LDH-Ce6 harnesses its glutathione oxidase (GSHOx)-like activity to deplete GSH, which in turn induces its own degradation within the TME and enables Ce6 release, collectively implementing a dual-action strategy that reinstates potent antitumor activity. Notably, released Mn 2+ ions activate the cGAS-STING pathway, promoting STING phosphorylation and interferon-mediated immunity. Through the integrated sonodynamic amplification of oxidative stress, pyroptosis induction, and cGAS-STING pathway activation, this nanoplatform effectively reverses immunosuppression and curbs tumor growth, thereby establishing an innovative design concept and a theoretical framework for combined sonodynamic therapy and immunotherapy.