Elevated glucose metabolism is an important hallmark of malignancy, and closely relates to cancer growth and progression, making it a promising target for cancer treatment. Herein, an adenovirus‐mimicking nanomachine (AMN) is developed for improving the management of malignancy, which has a unique core‐shell‐shell architecture consisting of gold nanorods (AuNR) and glucose oxidase (GOx) loaded zeolitic imidazolate framework‐8 (core) @ manganese dioxide mineralized albumin (BSA‐MnO₂) (interior shell) @ RGD peptide‐functionalized PEG (exterior shell). AMN selectively invades tumor cells and triggers metabolic competition to limit nutrient availability, which not only directly eliminates cancer cells, but enhances cancer response to the treatment. It is identified that AMN exhibits good photothermal efficacy, which significantly enhances GOx activity to kill cancer cells. Meanwhile, AMN triggers MnO₂ catalyzed oxygen generation, further improving GOx mediated starvation therapy, which greatly inhibits the expression of heat shock proteins and in turn enhances photothermal efficacy, resulting in synergistic anticancer effects. In vivo studies demonstrate that AMN selectively accumulates in the tumor and effectively eliminates the tumor without side‐effects. Notably, AMN exhibits trimodal imaging capability of photothermal, photoacoustic, and CT imaging, allowing for sensitively detecting tumors. Therefore, a promising anticancer strategy is provided by hijacking cellular glucose metabolism, which has great anticancer potential.