X-ray stimulates NQO1-dependent cascade reactions to induce strong immunogenicity for MRI-guided cancer radio-chemodynamic-immunotherapy.

Immunogenicity activation is vital for radioimmunotherapy, but the short-term oxidative damage caused by precise radiation planning limits this effect. Chemodynamic therapy (CDT) with prolonged generation of hydroxyl radical (•OH) can initiate immunogenicity in combination with X-rays, however, its performance is constrained by tumor insufficient H2O2. Here, we propose to construct β-lapachone-based nanoparticles (β-Lap/Fe NPs) which initiate cascade reactions to generate high levels •OH for an extended period in tumor following X-ray irradiation. β-Lap/Fe NPs, constructed by co-encapsulation of β-Lap and Fe3O4 nanoparticles in reactive oxygen species (ROS) responsive C16-S-mPEG2000 micelles, remain stable under normal conditions but rapid decompose and release β-Lap and Fe2+ when exposed to high level ROS. Upon X-ray irradiation, the upregulation of ROS and NAD (P) H: quinone oxidoreductase-1 (NQO1) in tumor cells accurately triggers β-Lap/Fe NPs to persistently generate high levels H2O2 and •OH for 12 hours, ultimately causing strong immunogenic cell death effects. Moreover, β-Lap/Fe NPs with excellent T2-weighted magnetic resonance imaging provide imaging reference for guiding precise X-ray radiation and predicting •OH generation. β-Lap/Fe NPs mediated radio-chemodynamic-immunotherapy remarkably against primary tumor growth, and further shows effective suppression on untreated distant tumors via the abscopal effect. In a word, this work proposed the simple but powerful strategy for cancer radio-chemodynamic-immunotherapy that combines X-ray and CDT to remote locally and visually actuated long-time production of H2O2 and subsequently persistent generation of •OH for initiating strong antitumor immune responses.