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 im-munosuppressive 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 (Gel@NPs) 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 me-tabolism 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.(c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

Dendritic cells (DCs) play a crucial role in the immune response against tumors, but their immunosuppressive cholesterol metabolism in tumors leads to dysfunctional DCs and limited antigen presentation. In this study, a metabolism nano-intervenor was developed to interfere with DCs' cholesterol metabolism and enhance antigen presentation. The system, consisting of DC-targeting nanoparticles and a hydrogel with sustained release, achieved precise and long-term immunometabolism intervention. Reprogramming DCs' metabolism significantly improved the efficacy of DC-mediated immunotherapy, especially in combination with immune-checkpoint inhibition induced by metformin hydrochloride (MET).