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 Mn²⁺. 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.