Nanosensitizer for Cancer Radioimmunotherapy via Anti‐IL‐35 Blockade Boosted Innate Immunity Activation

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.