Metastasis of breast cancer is key to poor prognosis and high mortality. However, the excess reactive oxygen species (ROS) and inflammatory response induced by photothermal therapy (PTT) further aggravate tumor metastasis. Meanwhile, the hypoxic tumor microenvironment promotes tumor cells to metastasize to distant organs. Herein, the intrinsic limitations of PTT for metastatic tumor have been addressed by fabricating polyethylene glycol modified iridium tungstate (IrWO x -PEG) nanoparticles. The as-designed IrWO x -PEG nanoparticles displayed good photothermal (PT) conversion ability for duplex photoacoustic/PT imaging guided PTT and multienzyme mimetic feature for broad-spectrum ROS scavenging. On the one hand, IrWO x -PEG effectively removed excess ROS generated during PTT and reduced inflammation. On the other hand, owing to the catalase-like activity, it preferentially triggered the catalytic production of oxygen by decomposing ROS, leading to relieving of the hypoxic microenvironment. Hence, under bimodal imaging guidance, IrWO x -PEG induced PTT completely eliminated in situ breast cancer in 4T1 tumor-bearing mice with no observable system toxicity, as well as further restricting tumor metastasis to other vital organs (lungs) by ROS scavenging, anti-inflammation, and regulating hypoxic microenvironment. We anticipate that this work will lead to new treatment strategies for other metastatic cancers.

Traditional starvation treatment strategies, which involve glucose oxidase and drug‐induced thrombi, often suffer from aggravated tumor hypoxia and have failed to improve antitumor efficacy in combination with oxygen‐dependent photodynamic therapy (PDT). Herein, glucose transporter 1 inhibitor genistein (Gen) and photosensitizer chlorin e6 (Ce6) are integrated to construct carrier‐free self‐assembled nanoparticles defined as GC NPs, for starvation therapy‐amplified PDT of tumor. GC NPs with regular morphology and stability are screened out by component adjustment, while the function of each component is preserved. On the one hand, Gen released from GC NPs can cut off tumor glucose uptake by inhibiting the glucose transporter 1 to restrict tumor growth, achieving starvation therapy. On the other hand, they are able to decrease the amount of oxygen consumed by tumor respiration and amplify the therapeutic effect of PDT. In vitro and in vivo experiments verify the excellent synergistic antitumor therapeutic efficacy of GC NPs without any apparent toxicity. Moreover, fluorescence and photoacoustic imaging provide guidance for in vivo PDT, demonstrating the excellent tumor enrichment efficiency of GC NPs. It is believed that this starvation therapy‐amplified PDT strategy by carrier‐free self‐assembled GC NPs holds promising clinical prospects.