Fractionated regimen-suitable immunoradiotherapy sensitizer based on ultrasmall Fe4Se2W18 nanoclusters enable tumor-specific radiosensitization augment and antitumor immunity boost

Abstract Immunoradiotherapy involving the combination of spatial control of radiotherapy and systemic survival of immunotherapy together has emerged as a promising strategy for both local and systemic tumor rejection. However, immunoradiotherapeutic efficacy is highly impeded by the radiation-induced immunosuppression and the insufficiency of antitumor immunity. Herein, ultrasmall Sandwich-type polyoxotungstate nanoclusters (Fe4Se2W18 NCs) with abundant high Z elements, efficient catalytic property, and unique electron structure are designed as the immunoradio-sensitizers. Apart from enhancing X-ray deposition for dose reduction, Fe4Se2W18 NCs exhibit tumor microenvironment-responsive catalytic activity, mainly through GSH depletion and Fenton reaction. Upon X-ray irradiation, Fe4Se2W18 NCs generate hydroxyl radical cascade to elevate tumor-specific oxidative stress, which can not only selectively ablate the local tumor but also effectively activate antitumor immune response. More importantly, ultrasmall Fe4Se2W18 NCs can be rapidly eliminated from the body, which can satisfy the needs of the fractionated regimen of radiotherapy clinically to reduce radiation-induced immunosuppression. Immune checkpoint inhibitor (anti-PD-L1 antibody) is further introduced into this system to boost a robust antitumor immunity, resulting in the inhibition of both primary and distant tumors. By presenting the Sandwich-type polyoxotungstate nanoclusters for immunoradiotherapy augmentation, this study is anticipated to establish a novel paradigm for immunoradio-sensitizer design based on polyoxometalate nanoclusters.