Metabolic reprogramming within the tumor microenvironment poses a significant obstacle to the therapeutic efficacy of antitumor immunity. Here, inspired by the diverse programme of cholesterol metabolism between tumor and immune cells, a biocompatible carboxy-modified cyclodextrin carrier equipped with a biomimetic surface was developed to encapsulate FX11 and Avasimibe (RM-CDC@FX11&Ava) for synergistic antitumor metabolic therapy and immunotherapy. Through the manipulation of calcium levels using poly-carboxylic compounds to initiate cholesterol biosynthesis, RM-CDC@FX11&Ava dynamically regulates glycolysis and blocks cholesterol esterification to navigate metabolic reprogramming. The resultant cholesterol augmentation triggered by RM-CDC@FX11&Ava could not only specifically induce 34.3 % tumor cell apoptosis but also promote 57.8 % dendritic cell maturation for antigen presentation and improve the effector function of T cells. Furthermore, the tumor immunosuppressive microenvironment was also reprogrammed by impairing Treg cells through the blockade of lactic acid. As a result, RM-CDC@FX11&Ava showed superior antitumor efficacy in mastadenoma and melanoma models.
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