METTL3介导的m6A修饰对肿瘤浸润髓系细胞功能的调控及机制研究

肿瘤浸润髓系细胞是肿瘤免疫逃逸的至关重要因素，但目前其活化的调控机制远未阐明。m6A修饰在多种生物学过程中发挥着重要作用，然而，对肿瘤浸润髓系细胞的调控作用尚未有研究。我们前期发现总m6A修饰水平及关键甲基化酶METTL3的表达在肿瘤浸润髓系细胞中显著增加，且METTL3在小鼠髓系细胞特异性缺失可导致肿瘤浸润髓系细胞免疫抑制功能下降，肿瘤生长减缓。初步的机制研究提示STAT信号激活所必需的JAK1可能是METTL3的m6A修饰底物。本项目拟利用髓系细胞缺失METTL3小鼠的肿瘤模型及体外细胞实验，深入研究m6A修饰对肿瘤浸润髓系细胞功能的调控及其分子机制，结合临床肿瘤样本，观察肿瘤浸润髓系细胞m6A修饰水平和METTL3的表达水平与肿瘤进展、治疗敏感性的相关性。研究结果有望为进一步揭示肿瘤的发生发展提供新的观点和视角，并为免疫治疗提供新的理论依据和潜在靶点。

Tumor-infiltrating myeloid cells contribute to tumor immune escape, but the regulatory mechanism of their activation is far from clear. m6A modification plays important roles in various cellular responses, however, it remains unknown whether the m6A modification controls the activation of tumor-infiltrating myeloid cells. Our previous research found that the total m6A modification level and the expression of the key methylase METTL3 significantly increased in tumor-infiltrating myeloid cells, and the specific deletion of METTL3 in mouse myeloid cells could inhibit the immunosuppressive function of tumor-infiltrating myeloid cells and suppress tumor growth. Mechanistically, JAK1, which is necessary for STAT signal activation, may be a m6A target of METTL3. This project intends to further study the effect and molecular mechanism of m6A modification on the function of tumor-infiltrating myeloid cells by using myeloid cell-deficient METTL3 mouse tumor model and in vitro cell experiments. Combined with clinical tumor tissue samples, the expression of METTL3 will be investigated, and the relationship between METTL3 and tumor progression, treatment sensitivity will be revealed. The results are expected to provide new perspectives for further revealing the mechanism of the occurrence and development of tumor, and provide new ideas and potential targets for cancer immunotherapy.