热量限制通过HIG2/ATGL通路调控中性粒细胞脂质代谢抑制肿瘤生长的机理研究

热量限制（CR）是具有明确抑瘤作用的饮食干预措施，然而长期CR引起的副作用限制了其在肿瘤康复及治疗中的应用，因此阐明CR的抑瘤机制成为其临床应用的突破口。前期研究中，我们在证实CR显著抑制小鼠胰腺癌和肺癌生长的基础上，通过单细胞测序对潜在免疫机制进行了全面分析，并结合功能实验首次揭示抑制中性粒细胞在CR抑瘤中的重要作用。中性粒细胞的促瘤作用逐渐被重视，而胞内脂质堆积导致的脂滴释放则是其重要的促瘤机制。进一步研究提示，CR可能下调中性粒细胞脂质代谢调控分子HIG2表达，进而上调脂质代谢酶ATGL促进脂质降解，从而阻碍其通过释放脂滴促进肿瘤细胞增殖、抑制抗肿瘤免疫的作用。本项目拟在上述研究的基础上，进一步解析CR通过调控中性粒细胞脂质代谢从而抑制肿瘤的分子机制，并探索其辅助免疫治疗的可能。本研究结果将对饮食干预调控肿瘤进展的机制有一全新的认识，有望为肿瘤康复及综合治疗提供策。

Caloric restriction (CR) is a dietary intervention with a clear anti-tumor effect. However, the side effects caused by long-term CR limit its application in cancer rehabilitation and treatment. To clarify the anti-tumor mechanism of CR has become a breakthrough in its clinical application, and it is also a hot spot in the research of diet intervention for inhibiting tumor. Based on the confirmation of the anti-tumor effect of CR on pancreatic cancer and lung cancer in mice, our previous experiments revealed for the first time the important role of neutrophil suppression in CR suppressing tumors through single-cell sequencing and functional analysis. The tumor-promoting effect of neutrophils is getting more and more attention, and the release of lipid droplets caused by lipid accumulation is a new mechanism of its tumor-promoting effect. Our further research suggests that CR can down-regulate the expression of neutrophil lipid metabolism regulating molecule HIG2, and then up-regulate fat metabolism enzyme ATGL to promote lipid degradation, thereby preventing it from releasing lipid droplets to promote tumor cell growth and inhibit anti-tumor immunity. This project intends to further analyze the molecular mechanism of CR by regulating the lipid metabolism of neutrophils to inhibit tumors on the basis of the above research, and explore the possibility of its adjuvant immunotherapy. This study will provide a new understanding of the mechanism of dietary intervention in regulating tumor progression, which is expected to provide new strategies for tumor rehabilitation and comprehensive treatment.