肝细胞癌
癌症研究
免疫疗法
转移
肿瘤微环境
免疫检查点
医学
热疗
免疫系统
内科学
癌症
免疫学
肿瘤细胞
作者
Ye Chen,Jiaxin Bei,Meijuan Chen,Weiguo Cai,Zutao Zhou,Mingyue Cai,Wensou Huang,Liteng Lin,Yongjian Guo,Mingyu Liu,Xinkun Huang,Zecong Xiao,Zhili Xu,Kangshun Zhu
标识
DOI:10.1002/adhm.202303031
摘要
Abstract Thermal ablation is a crucial therapeutic modality for hepatocellular carcinoma (HCC), but its efficacy is often hindered by the high recurrence rate attributed to insufficient ablation. Furthermore, the residual tumors following insufficient ablation exhibit a more pronounced immunosuppressive state, which accelerates the disease progression and leads to immune checkpoint blockade (ICB) resistance. Herein, evidence is presented that heightened intratumoral lactate accumulation, stemming from the augmented glycolytic activity of postablative residual HCC cells, may serve as a crucial driving force in exacerbating the immunosuppressive state of the tumor microenvironment (TME). To address this, an injectable nanoparticles‐hydrogel composite system (LOX‐MnO 2 @Gel) is designed that gradually releases lactate oxidase (LOX)‐loaded hollow mesoporous MnO 2 nanoparticles at the tumor site to continuously deplete intratumoral lactate via a cascade catalytic reaction. Using subcutaneous and orthotopic HCC tumor‐bearing mouse models, it is confirmed that LOX‐MnO 2 @Gel‐mediated local lactate depletion can transform the immunosuppressive postablative TME into an immunocompetent one and synergizes with ICB therapy to significantly inhibit residual HCC growth and lung metastasis, thereby prolonging the survival of mice postablation. The work proposes an appealing strategy for synergistically combining antitumor metabolic therapy with immunotherapy to combat postablative HCC recurrence.
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