FOXD1通过激活CaMKK2/AMPK通路介导巨噬细胞M2型极化促进肿瘤恶性进展及其机制研究

巨噬细胞向M2极化在肿瘤恶性进展中起着关键作用，但是肿瘤微环境调控巨噬细胞M2极化的分子机制尚未完全清楚。我们预实验结果显示FOXD1在肿瘤相关巨噬细胞中高表达，通过激活CaMKK2/AMPK通路促进巨噬细胞M2型极化。已有研究表明AMPK能通过降低mTOR和ACC活性抑制糖酵解和提高脂肪酸β氧化。糖酵解途径有利于巨噬细胞M1极化，而脂肪酸β氧化有利于巨噬细胞M2极化。因此，我们提出假设：FOXD1激活CaMKK2/AMPK通路，通过抑制mTOR和ACC活性介导细胞代谢重编程促进巨噬细胞M2型极化，进而促进肿瘤增殖和转移。本项目拟进一步通过体外和体内实验确定FOXD1诱导巨噬细胞M2型极化的分子机制及其介导的M2巨噬细胞促进肿瘤恶性进展的作用、相关机制和临床意义，为肿瘤的临床诊断和针对靶向巨噬细胞的有效抗肿瘤治疗策略提供科学依据。

M2 polarization of macrophages plays a key role in promoting tumor malignant progression. However, the molecular mechanism behind the polarization process under tumor microenvironment has not been fully understood. Our previous study demonstrated that FOXD1 was highly expressed in tumor-associated macrophages, and mediated M2 polarization of macrophages by activating CaMKK2/AMPK pathway. Previous studies have shown that AMPK could inhibit glycolysis and improve fatty acids β-oxidation by reducing mTOR and ACC activity. The glycolysis pathway could promote macrophage M1 polarization, while β-oxidation of fatty acids could promote macrophage M2 polarization. Therefore, we propose the hypothesis that FOXD1 promotes macrophage M2 polarization by activating CaMKK2/AMPK pathway, which could mediate cell metabolic reprogramming by inhibiting mTOR and ACC activity, and then promote tumor proliferation and metastasis. This project intends to further determine the molecular mechanism of M2 polarization of macrophages medicated by FOXD1, and the role, mechanism and clinical significance of the M2 macrophages mediated by FOXD1 in promoting tumor progression in vitro and in vivo, which provide a scientific foundation for clinical diagnosis of tumor and strategies of effective anti-tumor treatment of targeted macrophages.