Abstract

In situ tumor vaccination is preliminarily pursued to strengthen antitumor immune response. Immunogenic tumor cell death spontaneously releases abundant antigens and adjuvants for activation of dendritic cells, providing a paragon opportunity for establishing efficient in situ vaccination. Herein, Phy@PLGdH nanosheets are constructed by integrating physcion (Phy, an inhibitor of the pentose phosphate pathway (PPP)) with layered gadolinium hydroxide (PLGdH) nanosheets to boost radiation-therapy (RT)-induced immunogenic cell death (ICD) for potent in situ tumor vaccination. It is first observed that sheet-like PLGdH can present superior X-ray deposition and tumor penetrability, exhibiting improved radiosensitization in vitro and in vivo. Moreover, the destruction of cellular nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotide homeostasis by Phy-mediated PPP intervention can further amplify PLGdH-sensitized RT-mediated oxidative stress and DNA damage, which correspondingly results in effective ICD and enhance the immunogenicity of irradiated tumor cells. Consequently, Phy@PLGdH-sensitized RT successfully primes robust CD8 + -T-cell-dependent antitumor immunity to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors.