可欣
前蛋白转化酶
肝细胞癌
免疫疗法
免疫系统
癌症研究
医学
癌症
CD8型
癌症免疫疗法
肿瘤微环境
免疫学
内科学
胆固醇
脂蛋白
低密度脂蛋白受体
作者
Shiji Fang,Zheng Lu,Shu Gao,Xiaoxiao Chen,Xiaoju Guo,Yong Ding,Wenjing Yang,Jiale Chen,Zhongwei Zhao,Jianfei Tu,Minjiang Chen,Jiansong Ji
出处
期刊:ACS Nano
[American Chemical Society]
日期:2024-03-11
标识
DOI:10.1021/acsnano.3c11775
摘要
Immunotherapy is the most promising systemic therapy for hepatocellular carcinoma. However, the outcome remains poor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in altering cell-surface protein levels, potentially undermining the efficacy of immunotherapy against tumors. This highlights its potential as a target for antitumor therapy. Herein, CaCO3-based nanoparticles coencapsulated with DOX, an immunogenic cell death (ICD) inducer, and evolocumab was developed to enhanced the efficacy of immunotherapy. The obtained DOX/evolocumab-loaded CaCO3 nanoparticle (named DECP) exhibits a good capacity of acid neutralization and causes ICD of cancer cells. In addition, DECP is able to evaluate the cell-surface level of MHC-I, a biomarker that correlates positively with patients' overall survival. Upon intravenous injection, DECP accumulates within the tumor site, leading to growth inhibition of hepa1-6 bearing subcutaneous tumors. Specifically, DECP treatment causes augmented ratios of matured dendritic cells, tumor-infiltrating CD8+ T cells and natural killing cells, while concurrently depleting Foxp3+ regulatory T cells. Peritumoral delivery of DECP enhances the immune response of distant tumors and exhibits antitumor effects when combined with intravenous αPD-L1 therapy in a bilateral tumor model. This study presents CaCO3-based nanoparticles with multiple immunomodulatory strategies against hepatocellular carcinoma by targeting PCSK9 inhibition and modulating immune homeostasis in the unfavorable TME.
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