Radiotherapy-immunomodulated nanoplatform triggers both hypoxic and normoxic tumor associated antigens generation for robust abscopal effect and sustained immune memory.

Radiotherapy (RT) induced abscopal effect has garnered substantial attention, nevertheless, it is rarely observed in clinics, due to the tumor hypoxia-related radioresistance, inadequate immune stimulation, and immunosuppressive tumor microenvironment. Herein, we construct a radiotherapy-immunomodulated nanoplatform (THUNDER), which synergizes with RT and greatly triggers the generation of both hypoxic and normoxic tumor cells-derived tumor-associated antigens (TAAs), resulting in robust abscopal effect and sustained immune memory. THUNDER exhibits prolonged blood circulation and high tumor retention capacity. When combined with RT, THUNDER effectively destructs both hypoxic and normoxic tumor cells, facilitating the substantial release of TAAs from both cell types, which further promotes the maturation of dendritic cells (DCs), thus forming powerful immune stimulation and initiating systemic anti-tumor immunity. In murine models, the combination of THUNDER and RT efficiently suppresses the growth of triple-negative breast cancer. In addition, the further combination with PD-L1 blockade yields noteworthy suppression of distant metastasis and tumor recurrence, resulting in a 5.2-fold augmentation in CD8⁺ T lymphocytes within distant tumors and a 2.8-fold increase in effector memory T cells in the spleen. In conclusion, the radiotherapy-immunomodulated nanoplatform presents an effective strategy for combating tumor metastases and recurrence by eliciting both hypoxic and normoxic TAAs, offering a significant avenue for radioimmunotherapy.