以抗PD-1和PD-L1抗体为代表的免疫检查点阻断疗法解除了肿瘤细胞对T细胞的免疫抑制，释放T细胞的抗肿瘤活性，堪称人类肿瘤免疫治疗史上的里程碑。但由于这些方法仍存在诸多缺陷，亟需研发新的靶点和联合治疗方案以增强其疗效。丝氨酸代谢对T细胞功能极其重要，从中筛选新靶点，重编程T细胞代谢，用于肿瘤免疫治疗，在理论上可行。我们发现与代谢密切相关的Sirtuins家族成员SIRT7在调控T细胞丝氨酸代谢中有潜在的重要功能。本项目拟在构建T细胞条件敲除Sirt7基因小鼠模型基础上，解析SIRT7通过去琥珀酰化调控丝氨酸代谢途径关键酶SHMT2，影响其酶活性的分子机制，阐明SIRT7调控丝氨酸代谢在抗肿瘤免疫反应中的功能，探讨联合SIRT7小分子调节剂和免疫检查点阻断剂在肿瘤治疗中的效果。本项目从调控免疫细胞氨基酸代谢角度，为肿瘤免疫治疗提供新的视角，无论在基础研究还是潜在的临床应用上都有重要意义。

PD-1 is a receptor on T cells that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L1) and is suggested to play a role in the maintenance of self-tolerance. PD-L1 expressing on tumor cells confers a potent escaping mechanism from the host T cell immunity and raise the possibility that blockade of PD-1–PD-L1 interaction may provide an effective approach for tumor immunotherapy. Immune checkpoint therapy, especially anti PD-1, anti-PD-L1 and anti CTLA-4 antibody, has provided a very usful weapon against cancer. The goal of the therapy is not to activate the immune system to attack particular targets on tumor cells, but rather to remove inhibitory pathways that block effective antitumor T cell responses. .Given the limitation of current immune checkpoint therapy, the dynamic nature of immune responses to tumors, the complexity of regulation of expression of multiple immune checkpoints and their ligands, it may be difficult to rely on any single immunologic biomarker to treat tumors. It is urgent to identify new target and develop combination therapy to provide curative treatments for many patients..Serine metabolism is required for optimal T cell proliferation by fueling one-carbon metabolism and nucleotide biosynthesis. Furthermore, T cell metabolism has a central role in supporting and shaping immune responses and may have a key role in antitumor immunity. It is reasonable to uncover new targets for cancer immunotherapy and treatment from this pathway..Sirtuins are highly conserved NAD+-dependent protein deacylases. Recent studies have shed light on the critical roles of the seven mammalian sirtuins, SIRT1 to SIRT7, in energy metabolism. We found a link between SIRT7 and T cell serine metabolism.We are going to design four contents in this project. On the basis of generating mice with T-cell-specific depletion of Sirt7, we will study the mechanism of SHMT2 desuccinylated by SIRT7 and the consequence of this interaction in serine metabolic processes and the antitumour activity of T cells. By combination of small molecular of SIRT7 and immune checkpoint therapy , we hope to develop combination therapy to treat tumors. Our research will highlight SIRT7 as a candidate target for regulating T cell serine catabolism as a strategy to block tumor growth.