A Self-Enhancing Nanoreactor Reinforces Radioimmunotherapy by Reprogramming Nutrients and Redox Metabolisms

Altered metabolism of cancer cells reshapes the unique tumor microenvironment (TME) with glucose addiction and high antioxidant levels, resulting in a strong alliance to promote tumor progression and treatment failure. Herein, a Pd/Pt/Au tri-metallic mesoporous nanoparticle coated with pH-responsive tannic acid-iron ion (Fe(III)TA) network (PdPtAu@TF) is fabricated, aiming at reinforcing radioimmunotherapy by reprogramming nutrients and redox metabolisms. PdPtAu@TF has a fine hierarchical structure and demonstrates high glucose oxidase, peroxidase-, catalase- and glutathione peroxidase-mimic activities, acting as a self-enhancing nanoreactor to consume endogenous glucose and break redox homeostasis in the harsh TME. As a result, cancer cells accelerate the uptake of lipids, especially polyunsaturated fatty acids when glucose is deficient, and then fall into lipid peroxidation-induced ferroptosis trap to sensitize radiotherapy (RT), inhibiting tumor progression. More significantly, combined treatment with PdPtAu@TF can promote the polarization of pro-inflammatory M1-type macrophages as well as inhibit the proliferation of cancer-associated fibroblasts to overcome RT-induced immunosuppression and eliminate excessive tissue fibrosis, thereby eliciting antitumor immunity and suppressing tumor metastasis. Consequently, this study describes a promising strategy to enhance the efficacy of radioimmunotherapy by reprogramming tumor nutrients and redox metabolisms, which has great potential to benefit cancer treatments.