High‐ Z ‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination
High‐ Z ‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination
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高 Z 敏化放射治疗与戊糖磷酸途径的干预协同作用用于原位肿瘤疫苗接种
DOI：
10.1002/adma.202109726
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发表时间：
2022
影响因子：
29.4
通讯作者：
Yuan Ahu
中科院分区：
文献类型：
--
作者：
Wang Yuxiang;Chen Jing;Duan Rumeng;Gu Rong;Wang Weiran;Wu Jinhui;Lian Huibo;Hu Yiqiao;Yuan Ahu
肿瘤原位疫苗接种是加强抗肿瘤免疫应答的初步尝试。免疫原性肿瘤细胞死亡自发释放大量抗原和佐剂用于激活树突状细胞，为建立有效的原位疫苗接种提供了一个典范机会。在本文中，Phy@PLGdH纳米片通过将physcion（Phy，戊糖磷酸途径（PPP）的抑制剂）与层状氢氧化钆（PLGdH）纳米片整合来构建，以促进放射疗法（RT）诱导的免疫原性细胞死亡（ICD），用于有效的原位肿瘤疫苗接种。首次观察到片状PLGdH可以呈现上级的X射线沉积和肿瘤穿透性，在体外和体内表现出改善的放射增敏作用。此外，Phy介导的PPP干预对细胞内烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和核苷酸稳态的破坏可进一步放大PLGdH致敏的RT介导的氧化应激和DNA损伤，从而相应地导致有效的ICD并增强辐照肿瘤细胞的免疫原性。因此，Phy@PLGdH致敏的RT成功地引发了强大的CD 8 + T细胞依赖性抗肿瘤免疫，以增强针对原发性和转移性肿瘤的检查点阻断免疫疗法。
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.