Gemcitabine nano-prodrug reprograms intratumoral metabolism and alleviates immunosuppression for hepatocellular carcinoma therapy

High-rate aerobic glycolysis and abnormal glutamine metabolism in tumor cells lead to their unlimited malignant proliferation and induce immune escape in the tumor microenvironment. In this study, the GLS1 inhibitor BPTES and the PDHC inhibitor CPI-613 were co-delivered by an ROS-sensitive GEM nano-prodrug (PD-G@BC), and a simultaneous inhibition of glycolysis and glutamine metabolism was achieved to deprive tumor cells of nutrient supply. In addition, this metabolism reprogramming effectively weakened the sources of glucose and glutamine in tumor cells, correspondingly thrived metabolism in antitumor immune cells, thereby increasing the intratumoral infiltration and functions of the immunogenic cells to alleviate the immunosuppressive responses. This multifunctional combination strategy will provide new insights into the design of synergistic cancer immunotherapy based on metabolic interventions.