Abstract
The cGAS-STING signaling pathway has emerged as a promising target for cancer immunotherapy. However, STING agonists have a dual-edged nature. Although they enhance antitumor T cell activity, STING agonists also elicit protumorigenic effects by promoting IL-35-producing B regulatory (Breg) cells, suppressing natural killer (NK) cell density, and fostering immune suppression. To address these challenges, this work develops a tumor microenvironment-responsive hollow mesoporous nanosystem that degrades under high glutathione conditions, thereby releasing the STING agonist MSA-2 and Mn ions. This nanosystem facilitates magnetic resonance imaging-guided chemodynamic therapy and radiosensitization, efficiently activating the cGAS-STING pathway by disrupting mitochondrial and nuclear DNA. Notably, by integrating this nanosystem with an anti-IL-35 blockade, this work successfully mitigates the Breg cell-mediated suppression of NK cells, restores innate immune responses, and enhances antitumor efficacy. This study highlights the pivotal role of anti-IL-35 in reversing immunosuppression, enhancing innate immunity, and establishing a synergistic theranostic platform for molecular imaging-guided cancer radioimmunotherapy.