Immunostimulant In Situ Hydrogel Improves Synergetic Radioimmunotherapy of Malignant Glioblastoma Relapse Post‐Resection

Abstract Tumor recurrence remains the major cause of management failure after surgical resection of glioblastoma (GBM). Immunotherapy has the potential to effectively eradicate tumors and trigger immune memory to prevent tumor recurrence but not improve the outcomes of GBM patients. Here, an injectable, reactive oxygen species‐degradable therapeutic hydrogel (ADU‐AAV‐PD1@Gel), capable of sustained local release of soluble PD‐1 (sPD‐1) and stimulator of interferon gene (STING) agonist ADU‐S100 (ADU), is developed and applied in a GBM surgical resection model. Adeno‐associated virus serotype 9 is employed to stably express sPD‐1 blocking the PD‐1/PD‐L1 pathway. Concomitantly, the released ADU activates the STING pathway to improve tumor immunogenicity and response to therapy. This therapeutic hydrogel combined with radiotherapy (RT) effectively promotes sustained T cells infiltration and restores T cells effector function, which exhibits a robust antitumor immune response and significantly suppresses tumor growth. Moreover, ADU‐AAV‐PD1@Gel combined with RT treatment can also induce a long‐term immune memory to prevent GBM recurrence. As a result, ADU‐AAV‐PD1@Gel provides a novel strategy for effective radioimmunotherapy of GBM relapse post‐resection.