Therapeutic hydrogel for enhanced immunotherapy: A powerful combination of MnO2 nanosheets and vascular disruption

Vascular disruption-based tumor starvation therapy efficacy is negatively affected by potential hypoxia-induced immunosuppression. Herein, MnO 2 nanosheets with Fenton-like catalytic activity and immunogenic cell death induction activity were chosen as complementary components to overcome the above bottleneck of vascular disruption therapy. Based on this, we developed a therapeutic hydrogel (CM@Gel) that co-encapsulates MnO 2 nanosheets and the vascular disrupting agent CA4P to exacerbate tumor starvation and enhance immunotherapy. Moreover, the form of hydrogel via local administration contributes to durable drug release while avoiding potential adverse events of vascular disruption when systemically administered. In the breast cancer animal model, the prepared CM@Gel not only alleviates hypoxia after selectively blocking tumor nutrient sources but also transforms the immunosuppressive tumor environment into an immunoactive phenotype. CM@Gel can also dramatically potentiate the efficacy of immune checkpoint therapy (ICB) on the condition of tumor starvation, further verifying its potential as an antitumor immunity booster. This study provides a unique synergistic strategy of tumor starvation therapy and immunotherapy, leveraging a powerful combination of MnO 2 nanosheets and vascular disruption. • The therapeutic hydrogel was prepared for enhanced anti-tumor immunotherapy. • Vascular disruption agent CA4P blocks tumor lifeblood and seldom impacts the normal vasculature. • MnO 2 nanosheets reverse hypoxia and immunosuppression by Fenton-like catalytic activity and immunogenic cell death effect. • The combination of MnO 2 nanosheets and vascular disruption exerts an excellent synergism effect. • The form of hydrogel via local administration contributes to durable drug release and lower potential adverse events.