Bimetallic Oxide FeWOXNanosheets as Multifunctional Cascade Bioreactors for Tumor Microenvironment-Modulation and Enhanced Multimodal Cancer Therapy

Modulating the hostile tumor microenvironment (TME) rather than directly killing cancer cells may be an effective strategy to improve the therapeutic benefits in cancer treatment. Herein, FeWO(X)nanosheets are constructed as cascade bioreactors to modulate the TME and enhance radiotherapy and immunotherapy of tumors. Synthesized by the thermal-decomposition method and modified by poly(ethylene glycol) (PEG), the obtained FeWOX-PEG with multivalent metal elements (Fe2+/3+, W5+/6+) exhibit efficient catalytic decomposition of hydrogen peroxide (H2O2) to generate hydroxyl radicals (center dot OH) for chemo-dynamic therapy (CDT). The generated high valence of metal ions (Fe3+/W6+) in FeWOX-PEG are reduced by endogenous glutathione (GSH), both leading to depletion of GSH and further amplified oxidative stress, and resulting in the reduced metal valence statuses (Fe2+/W5+) enabling cascade bioreactions. Such FeWOX-PEG bioreactors enhance the oxidative stress in the tumor and interact with X-rays, significantly improving cancer radiotherapy (RT). Furthermore, the reactive oxygen species (ROS)-induced inflammation caused by FeWOX-PEG in TME activates the immune system and promotes the tumor-infiltration of various types of immune cells, which working together with cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint blockade could elicits a robust immune response to defeat tumors.