Single cancer starvation therapy (ST) strategy can’t achieve satisfactory anti-tumor effect, mainly due to the 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 starvation therapy as well as reinforced photothermal therapy (PTT) and chemodynamic therapy (CDT). After CADCR NPs were targeted to tumor cells, CaCO3 was ruptured in the acidic environment, releasing Ca2+ to chelate glutamine and cutting off the glutamine metabolic pathway of the tumor. 2-DG was also released from mesoporous SiO2 and restrained the glycolytic pathway of tumor cells. In addition, under the thermal stimulus of near-infrared irradiation, axitinib was released from CuS NPs, which inhibited the proliferation 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 promoted the transformation of macrophages from M2 to M1 type, increasing the expression of CD8+ T cells in the tumor site. In conclusion, CADCR NPs achieve severe tumor starvation by simultaneously interfering with 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.