Single cancer starvation therapy (ST) strategy can’t achieve satisfactory anti-tumor effect, mainly due tothe diversified nutritional sources of tumor cells. Herein, CuS@Axitinib-SiO2@2-Deoxy-D-glucose(2-DG)-CaCO3-RGD nanoparticles (CADCR NPs) were prepared for three-pathway blocking for efficient starvationtherapy as well as reinforced photothermal therapy (PTT) and chemodynamic therapy (CDT). AfterCADCR NPs were targeted to tumor cells, CaCO3 was ruptured in the acidic environment, releasingCa2+ to chelate glutamine and cutting off the glutamine metabolic pathway of the tumor. 2-DG was alsoreleased from mesoporous SiO2 and restrained the glycolytic pathway of tumor cells. In addition, underthe thermal stimulus of near-infrared irradiation, axitinib was released from CuS NPs, which inhibited theproliferation of tumor blood vessels, ultimately inhibiting the aerobic respiratory pathway of tumor cells. Interestingly, CADCR NPs also showed potential to reshape the tumor microenvironment (TME) and promotedthe transformation of macrophages from M2 to M1 type, increasing the expression of CD8+ T cellsin the tumor site. In conclusion, CADCR NPs achieve severe tumor starvation by simultaneously interferingwith three energy metabolic pathways, and further enhance tumor treatment with the aid of PTT,CDT, and TME improvement, which exhibits great potential for clinical cancer therapy.