MAGL-CB2/TLR4诱导M1极化在NSCLC肝脏转移灶免疫微环境中的作用和机制研究

肝脏是NSCLC转移的常见部位，免疫检查点抑制剂对其疗效普遍较差，生物标志物发现和治疗策略优化是目前临床亟待解决的关键问题。针对这一临床重大需求，申请者开展了前期研究并发现：合并脂质代谢异常（非酒精性脂肪肝病）的肝转移患者疗效显著优于对照组，脂质组学分析发现这类患者MAGL表达显著升高；肿瘤微环境中M1/M2巨噬细胞比例增加，CD8+T细胞的浸润增多。结合既往研究发现MAGL可抑制CB2/TLR4通路，诱导肿瘤相关巨噬细胞M1极化，提出如下假说：“脂肪酸代谢异常导致肿瘤相关巨噬细胞MAGL高表达，通过CB2/TLR4诱导M1型极化，促进CD8+T细胞的活化，介导抗肿瘤免疫”。本项目拟应用细胞、动物模型及临床样本队列研究，阐明MAGL调控NSCLC肝转移灶免疫微环境的分子机制。本项目不但为NSCLC合并肝转移患者人群精准免疫治疗实施提供科学依据；也将为免疫治疗策略优化提供线索。

Liver is the common site of NSCLC metastasis, and the efficacy of immune check point inhibitors is generally poor. Biomarker discovery and treatment strategy optimization are the key problems to be solved in clinical practice. In response to this clinical significant demand, we carried out a preliminary study and found that: the efficacy of liver metastasis patients with abnormal lipid metabolism (non-alcoholic fatty liver disease) was significantly better than that of the control group, and the lipomics analysis found that the expression of MAGL was significantly increased in these patients; the proportion of M1/M2 macrophages in the tumor microenvironment increased, and the infiltration of CD8 + T cells increased. According to previous studies, MAGL can inhibit CB2/TLR4 pathway and induce M1 polarization of tumor-related macrophages. The hypothesis is as follows: "abnormal fatty acid metabolism leads to high expression of MAGL in tumor-related macrophages. Through CB2 /TLR4, M1 polarization can be induced, CD8 + T cell activation can be promoted and anti-tumor immunity can be mediated". In this project, cell model, animal model and clinical sample cohort were used to study the molecular mechanism of MAGL regulating immune microenvironment of NSCLC with liver metastasis. This project will not only provide scientific basis for the implementation of precise immunotherapy for NSCLC patients with liver metastasis, but also provide clues for the optimization of immunotherapy strategies.