我们发现代谢应激促进SENP1进入线粒体中，调控Sirt3的SUMO修饰和活性及相关线粒体的代谢。进一步发现Sirt3 SUMO位点突变的小鼠免疫细胞活性改变，并与肿瘤生长相关。基于此，我们假设Sirt3的SUMO修饰能够调控免疫细胞线粒体代谢和功能，在肿瘤微环境的作用下，SENP1调控Sirt3的SUMO修饰，进而影响抗肿瘤免疫和肿瘤生长。本课题将研究以下问题：1）SENP1-Sirt3轴能够调控巨噬细胞和T细胞哪些功能？ 2）SENP1-Sirt3轴能够调控巨噬细胞和T细胞中哪些代谢途径？3）肿瘤微环境有哪些代谢应激因素能够及如何调控SENP1-Sirt3轴的活性？4）SENP1-Sirt3轴对抗肿瘤免疫的调控作用是否与肿瘤病理过程有关？这些研究将明确SENP1-Sirt3轴在调控免疫细胞代谢及抗肿瘤免疫中的作用与机制。

We previously found that deacetylase Sirt3 catalytic activity was suppressed by SUMOylation in mitochondria. During metabolic stress, SUMO-specific protease SENP1 was accumulated in mitochondria and quickly de-SUMOylated and activated Sirt3, which modulated metabolic program in mitochondria. We also demonstrated that the mice with SUMOylation deficiency altered the function of immune cells. Meanwhile, xenograft tumor in the mice with SUMOylation deficiency grew faster than that in control mice. Therefore, we hypothesize that tumor microenvironment triggers SENP1-Sirt3 axis in immune cells, which undergo metabolic reprogramming and modulates anti-tumor immunity. We will perform experiments to determine: 1) the role of SENP1-Sirt3 axis in regulation of immune activities in T cells and macrophages; 2) the role of SENP1-Sirt3 axis in modulating metabolic program in T cells and macrophages; 3) How tumor microenvironment triggers SENP1-Sirt3 axis in immune cells; 4) the role of SENP1-Sirt3 axis in modulating anti-tumor immunity of immune cells during tumorigenesis. These studies will provide us insight into metabolic reprogramming in immune cells in anti-tumor immunity.