High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

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.