Injectable PROTAC-loaded hydrogel remodels the tumor microenvironment to potentiate radio-immunotherapy

Radiotherapy (RT) is a key component of comprehensive cancer treatment regimens; nevertheless, its concomitant immunosuppression may diminish therapeutic efficacy. In this study, we developed an injectable hydrogel system for the local delivery of PROteolysis TArgeting Chimeras (PROTACs), achieved by loading tumor cell membrane-fused liposome nanoparticles to enhance the anti-tumor effect. The system targeted Bromodomain-containing protein 4 (BRD4), and combined treatment with RT promoted DNA damage, reduced DNA repair and decreased tumor cell proliferation and survival. Additionally, this strategy effectively promoted dendritic cell (DC) maturation, enhanced tumor-specific T cell infiltration, reversed radiotherapy-induced immunosuppression and boosted the anti-tumor immune response. This strategy expands the application of PROTAC technology in counteracting radiotherapy-induced immunosuppression and provides an important basis for subsequent biomedical translation and clinical development.