肿瘤微环境中NK细胞的功能耗竭不仅是肿瘤免疫逃逸的关键原因，也是制约肿瘤免疫治疗效果的重要因素。申请人前期研究发现胆固醇代谢参与自然杀伤（NK）细胞的抗肿瘤功能调控，而肿瘤浸润NK细胞的胆固醇代谢状态，及其是否参与NK细胞功能耗竭目前未见报道。项目前期实验表明肿瘤浸润NK细胞胆固醇含量显著下降，胆固醇代谢发生紊乱，其中，介导胆固醇外流的关键分子ATP结合盒转运体G1（ABCG1）表达异常上调。在NK细胞中过表达ABCG1可明显降低细胞胆固醇水平，并抑制其抗肿瘤功能，提示ABCG1可能参与了肿瘤浸润NK细胞的功能耗竭和肿瘤免疫逃逸。申请人拟利用基因工程小鼠及细胞系，采用小鼠化学诱癌、皮下荷瘤及肺转移瘤模型构建、NK细胞过继治疗等体内外实验，系统研究ABCG1对NK细胞抗肿瘤功能的调控作用和机制，并对ABCG1的靶点治疗价值进行初步探讨，有望为肿瘤的免疫治疗提供新的思路和策略。

The functional exhaustion of NK cells in tumor microenvironment is not only the key reason for tumor immune escape, but also an important factor restricting the effect of tumor immunotherapy. Previous studies of applicants have found that cholesterol metabolism is involved in the regulation of anti-tumor function of natural killer (NK) cells, but the status of cholesterol metabolism in tumor-infiltrating NK cells and whether it is involved in NK cell function depletion has not been reported. In this project, it was found that the cholesterol content of tumor infiltrating NK cells decreased significantly and cholesterol metabolism was disordered, in which the expression of ATP-binding cassette transporter G1 (ABCG1), a key molecule mediating cholesterol efflux, was abnormally up-regulated. Overexpression of ABCG1 in NK cells can significantly reduce cellular cholesterol level and inhibit its anti-tumor function, suggesting that ABCG1 may be involved in the exhaustion of tumor infiltrating NK cells and tumor immune escape. In this study, genetically engineered mice and cell lines were used to study the regulation and mechanism of ABCG1 on the anti-tumor function of NK cells in vivo and in vitro, to explore the possibility of ABCG1 as a target for tumor therapy, which is expected to provide new ideas and strategies for tumor immunotherapy.