Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers. However, when glycolysis is inhibited, tumor cells will break down glutamine as the raw material for the replenishment pathway to maintain the tricarboxylic acid cycle ensuring energy supply, therefore inducing ineffective interruption of metabolic. Herein, we designed glutamine transporter antagonist l-γ-glutamyl-p-nitroanilide (GPNA) loaded and 4T1 cancer cell membrane coated iridium oxide nanoparticles (IrO₂-GPNA@CCM) to realize a comprehensive inhibition of tumor energy supply which synergistically mediated by glycolysis and glutamine cycle. IrO₂ NPs were used to catalyze the O₂ generation by facilitating the decomposition of endogenous H₂O₂ in tumor cells, which further downregulated the expression of HIF-1α and PI3K/pAKT to interrupt the generation of lactate. Meanwhile, the loaded GPNA was released under NIR irradiation to bind to alanine-serine-cysteine transporter (ASCT2) for glutamine uptake suppression, therefore realizing the comprehensive dysfunction of cell metabolism. Moreover, both in vitro and in vivo results convinced the thorough energy inhibition effect based on IrO₂-GPNA@CCM NPs, which provided an inspiring strategy for future construction of tumor therapeutic regimen.