肿瘤细胞利用糖酵解产生能量和代谢中间物赋予其自身内在生长优势，新近研究表明这种Warburg效应还为肿瘤细胞提供一种外部优势：肿瘤造成的代谢限制，重组了免疫细胞代谢状态，抑制了免疫细胞活性和抗肿瘤能力。那么是否可以通过重编程免疫细胞代谢，彻底解放被肿瘤抑制的免疫系统，构建肿瘤治疗新方式？SIRT5是与代谢密切相关的赖氨酸去酰基化酶。我们研究发现：SIRT5可以抑制肿瘤细胞代谢；抑制巨噬细胞糖酵解和小鼠结肠炎。鉴于巨噬细胞在结肠炎癌转化中的重要作用，我们提出SIRT5是否通过协调肿瘤代谢和免疫代谢平衡，调控结肠癌发生发展？本项目拟构建Sirt5条件敲除小鼠结肠炎癌模型、解析结肠炎癌转化三个关键阶段的巨噬细胞代谢格局、调控SIRT5活性“重编程”巨噬细胞代谢以抑制结肠癌等，来研究SIRT5调控免疫代谢在结肠癌中的功能和机制。本研究将深入阐明免疫代谢在肿瘤中的作用机理，从而为肿瘤治疗提供新方法。

The Warburg effect of cancer cell is the ability to acquire glucose from a frequently nutrient-poor environment and utilize these glucose to both maintain ATP and build new biomass. Metabolic competition of tumor cells and TILs(tumor infiltrating lymphocytes) within the tumor niche directly dampen TILs’s effector function and allowing tumor progression. Is it possible to correct this resource imbalance through reprogramming immune cells metabolism? The deacylase sirtuin 5 (SIRT5) catalyzes the removal of lysine malonylation, succinylation, and glutarylation from a wide range of proteins in different metabolic pathways. We found the emerging role of SIRT5 in tumor metabolism regulation, macrophage metabolism, dextran sodium sulfate-induced colitis in mice and downregulation in colitis-associated cancer (CAC). However, the regulation of immunometabolism and inflammation by SIRT5 independent of their role in modulating tumor metabolism remains largely unknown. We think the SIRT5 has an important role in CAC by regulating resource imbalance in the tumor microenvironment. Here, we are going to discover the function and mechanism of SIRT5 in progression of CAC. The first part is to induce CAC model in wild type and Sirt5 knockout mice ( myeloid cell specific knockout) by dextran sulfate sodium (DSS) plus azoxymethane (AOM). The second part is to characterize the metabolism of tumor associated macrophages (TAMs) in different stage of CAC. The last part is to determine functional consequence of metabolic rearrangement by regulating SIRT5 function and activity.. New efforts to target cancer should incorporate the idea that metabolic competition occurs in tumors and this can influence tumor progression. Future therapies may consider combining treatments that dampen tumor metabolism with those that enhance TILs nutrient acquisition in order to promote optimal antitumor immunity.