Reprogramming dysfunctional dendritic cells by a versatile metabolism nano-intervenor for enhancing cancer combinatorial immunotherapy

Dendritic cells (DCs) are crucial for the orchestration of anti-tumor immune response. However, the immunosuppressive cholesterol metabolism of DCs in tumor sites induces dysfunction of DCs and limited antigen presentation. Herein, a metabolism nano-intervenor of DCs (Man-OVA(RSV) NPs) was loaded in a versatile hydrogel system ([email protected]) based on the gelation reaction between graphene oxide (GO) and metformin hydrochloride (MET). The nanoparticle packaged rosuvastatin (RSV) interfered with cholesterol metabolism of DCs to reduce antigen degradation, thereby enhancing antigen presentation. Due to the DC targeting ability of mannose decoration on NPs and durable releasing profiles of hydrogel, the system achieved precise and long-term immunometabolism intervention of DCs. Moreover, reprogramming metabolism of DCs could significantly restore the efficacy of DC-mediated immunotherapy and combine with immune-checkpoint inhibition induced by MET to significantly improve therapeutic outcomes. Collectively, reprogramming cholesterol metabolism of DCs may be a potential strategy to ameliorate the malfunctional DCs and evoke robust anti-tumor immunity.