Semiconducting Polymer Nanotransducers Reinvigorate Antitumor Immunity Through Amplifying Radio/Chemodynamic Therapy in Orthotopic Glioma

Abstract Despite advances in therapeutic options for glioma, clinical outcomes remain unsatisfactory due to the blood‐brain barrier (BBB) and tumor microenvironment with immunosuppression. Herein, a semiconductor polymer (SP)‐based nanotransducer (TM@SPN S ) is developed for enhanced radio/chemodynamic therapy (RDT/CDT) to restore antitumor immunity in an orthotopic glioma model. The nanotransducer is formed through self‐assembly of a SP while encapsulating of adenosine A2A receptors (A2AR) antagonist SCH58261, then functionalized the surface with a transferrin‐manganese dioxide complex (TM). After crossing the BBB and targeting glioma via transferrin modification, TM@SPN S triggers the generation of singlet oxygen under X‐ray irradiation and produces hydroxyl radicals through a Fenton‐like reaction mediated by Mn 2+ . This dual reactive oxygen (ROS) generation synergistically enhances RDT/CDT efficacy and amplifies the immunogenic cell death (ICD). Concurrently, the released SCH58261 competitively inhibits A2AR, thereby reversing adenosine‐induced immunosuppression within the TME. Results demonstrate that this combinatory strategy markedly enhances treatment efficacy, achieving 100% survival at day 30 in orthotopic glioma models. This outcome is significantly superior to those of control groups lacking X‐ray irradiation, SCH58261, or TM components. By integrating amplified RDT/CDT with blockade of A2AR, this study achieves concurrent induction of a localized ROS storm and immune reactivation, offering a novel therapeutic strategy for treatment‐resistant glioma.