传出细胞增多
梅尔特克
肿瘤微环境
癌症研究
免疫系统
医学
转移
巨噬细胞
癌症
免疫检查点
免疫疗法
免疫学
结直肠癌
生物
受体
内科学
受体酪氨酸激酶
体外
生物化学
作者
Xuefei Zhou,Dezhi Li,Shenglong Xia,Xixi Ma,Rong Li,Yongli Mu,Zimo Liu,Lu Zhang,Quan Zhou,Wei Zhuo,Kefeng Ding,Aifu Lin,Wei Liu,Xiangrui Liu,Tianhua Zhou
标识
DOI:10.1016/j.jconrel.2023.12.018
摘要
Tumor-associated macrophages play pivotal roles in tumor progression and metastasis. Macrophage-mediated clearance of apoptotic cells (efferocytosis) supports inflammation resolution, contributing to immune evasion in colorectal cancers. To reverse this immunosuppressive process, we propose a readily translatable RNA therapy to selectively inhibit macrophage-mediated efferocytosis in tumor microenvironment. A clinically approved lipid nanoparticle platform (LNP) is employed to encapsulate siRNA for the phagocytic receptor MerTK (siMerTK), enabling selective MerTK inhibition in the diseased organ. Decreased MerTK expression in tumor-associated macrophages results in apoptotic cell accumulation and immune activation in tumor microenvironment, leading to suppressed tumor growth and better survival in both liver and peritoneal metastasis models of colorectal cancers. siMerTK delivery combined with PD-1 blockade further produces enhanced antimetastatic efficacy with reactivated intratumoral immune milieu. Collectively, LNP-based siMerTK delivery combined with immune checkpoint therapy may present a feasible modality for metastatic colorectal cancer therapy.
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