肿瘤微环境中浸润的FOXP3+调节性T细胞（Tregs）是阻碍免疫疗法如PD-1抗体等发挥作用的一大障碍，如何破坏肿瘤浸润Treg细胞的免疫抑制功能以调动抗肿瘤免疫是实现更高效肿瘤免疫治疗的重要方向。我们前期通过单细胞测序技术研究Treg细胞在炎症因子IL-6刺激下的基因表达谱，发现甘油激酶GK是Treg细胞维持其功能稳定性的关键基因，且通过体外实验证实敲低GK可以削弱Treg细胞抑制功能并降低其表面CTLA-4和GITR等功能性标志物表达；此外在结肠癌单细胞测序数据库中GK高表达于功能性Treg而非静息Treg细胞亚群中。据此我们推测Treg细胞可能通过上调代谢酶GK以增强其在肿瘤微环境中的代谢适应性并维持其功能稳定性。本项目旨在阐明GK调控肿瘤浸润Treg细胞功能稳定性的分子机制及其对肿瘤免疫耐受的影响，以期为针对Treg细胞的肿瘤免疫治疗新策略提供依据。

The infiltrated FOXP3+ regulatory T cells (Tregs) in tumor microenvironment is undermining the anti-tumor immunity and limits the efficacy of immunotherapies including PD-1 antibody. How to selectively downregulate the immunosuppressive function of tumor infiltrating Tregs, therefore, to release the anti-tumor immune response has been considered as one of the most important approaches to achieve a more effective outcome of tumor immunotherapy. We previously investigated the gene expression profile of Tregs under IL-6 stimulation at single-cell level by single cell mRNA sequencing analysis. Our preliminary data identified glycerol kinase (GK) that highly expressed in the stable Treg subgroup was critical to maintain the functional stability of Treg. Interestingly, knockdown of GK in Tregs resulted in the inhibition of Tregs’ suppressive activity against Teff cells alongside with the reduced CTLA-4 and GITR expressions. In addition, in the open database of single cell sequencing on lymphocytes derived from colon cancer tissue, GK is highly expressed by suppressive Treg cells but not resting Treg cells. Collectively, we hypothesize that tumor infiltrating Tregs may elevate the expression of GK to shape the metabolic adaption and keep functional stability in tumor microenvironment. The aim of this project is to clarify the molecular mechanism underlying the regulation of GK on the stability of Treg cells and tumor immune tolerance. The findings would provide evidences for novel tumor immunotherapy strategies related to the regulation of Treg cells.