RNA-based modulation of macrophage-mediated efferocytosis potentiates antitumor immunity in colorectal cancer
JOURNAL OF CONTROLLED RELEASE(2024)
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, lead-ing 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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关键词
Tumor-associated macrophage,Efferocytosis,Lipid nanoparticle,Colorectal cancer,Immune checkpoint blockade
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