肿瘤相关巨噬细胞(TAM)被视为M2样TAM，具有促肿瘤作用。研究表明，巨噬细胞(Mφ)具有可塑性，将TAM再教育成抗肿瘤的M1样TAM已成为肿瘤治疗新策略。然而，调控TAM表型转变的分子机制尚不完全清楚。我们前期工作显示Notch信号可通过其下游的miRNAs调控Mφ极化。其中，miR-99b-5p可促进M1型Mφ极化。在体内靶向TAM递送miR-99b发现，其能够将TAM再教育成M1样TAM，抑制肝癌进展，提示：miR-99b可能是Notch信号下游再教育TAM进行肝癌治疗的关键分子。本课题将利用Mφ特异阻断/激活Notch信号的小鼠结合肝癌模型，揭示miR-99b介导Notch信号调控Mφ极化和功能的机制并在临床标本上验证；利用纳米技术靶向TAM递送miR-99b，探究miR-99b介导Notch信号治疗肝癌的作用机制。本课题有望为再教育TAM进行肝癌免疫治疗提供新靶点。

Tumor-associated macrophages (TAM) are considered as M2-like TAM that play a critical role in tumor progression. Recently, many studies show that macrophages possess high plasticity. Re-educating TAM to switch to anti-tumor M1-like TAM could be a very promising strategy for tumor therapy. However, the underlying mechanisms on how to remodel TAM phenotype still remain unclear. Our previous studies have reported that Notch signaling can promote M1 macrophage polarization by regulating a series of miRNAs. Therein, miR-99b-5p was found to participate in regulating M1 macrophage polarization. Delivery miR-99b-5p into TAM could re-educate TAM to switch to M1-like TAM leading to tumor growth retardation. All these results suggest that miR-99b-5p might be one key downstream molecule of Notch signaling for TAM re-education-mediated liver cancer treatment. Therefore, using some genetically modified mice, such as myeloid-specific Notch activation/blockade mice, and different liver cancer models, we will explore the molecular mechanism of Notch signaling regulating macrophage polarization and function via miR-99b-5p, and verify the correlation between Notch/miR-99b-5p/target genes axis and liver cancer progression using clinical samples. Furthermore, taking advantage of nanotechnology, we will delivery miR-99b-5p into TAM and investigate their role for liver cancer therapy. This project hopefully provides new targets for liver cancer treatment based on TAM re-education.