Hyaluronic acid and polyvinyl alcohol-based radioresponsive hydrogel for combined radioimmunotherapy of breast cancer bone metastasis.

Combining radiotherapy with immunotherapy holds promise for treating solid tumors and metastases, but challenges persist, including hypoxia-induced immunosuppression and immune-related adverse events from off-target toxicity. To address this, we engineered an in-situ formed hydrogel by crosslinking hyaluronic acid and polyvinyl alcohol with a reactive oxygen species (ROS)-responsive linker (3-aminophenylboronic acid). This hydrogel leverages radiotherapy-induced ROS within the tumor microenvironment to trigger localized release of nitric oxide (NO) and the toll-like receptor 7/8 (TLR7/8) agonist R848. NO normalizes hypoxic tumor vasculature, while R848 amplifies radiotherapy-initiated antitumor immunity. In breast cancer and bone metastasis models, this radioimmune-regulated hydrogel significantly enhanced tumor normoxia, promoted dendritic cell maturation, and primed CD8+ T cells, substantially improving the efficacy of combined radioimmunotherapy. Our study highlights a potent hydrogel-based strategy to overcome key limitations in advanced cancer therapy.