巨噬细胞作为固有免疫应答的核心成分，虽具有强大的抗肿瘤潜质，但受肿瘤教育反而转变为促进肿瘤发展的M2型巨噬细胞。目前M2型肿瘤相关巨噬细胞已成为肿瘤免疫治疗的新靶点，但仍缺乏理想手段。已有研究指出，M1与M2巨噬细胞糖代谢途径存在明显差异。申请人的前期研究结果也表明，巨噬细胞M1表型受糖原代谢的调控，增强巨噬细胞糖原代谢有望将M2巨噬细胞逆转为M1巨噬细胞。基于此，本项目提出假设：通过碳酸锂抑制GSK-3β，恢复糖原合酶Gys1活性，增加糖原合成，进而将肿瘤相关的M2型巨噬细胞再教育成为抗肿瘤的M1型巨噬细胞。本项目拟对不同巨噬细胞亚群，分析碳酸锂对其表型和功能的影响，进而阐明其内在分子机制，同时探究碳酸锂通过对M2型巨噬细胞的再教育，对肿瘤免疫微环境的重塑及其抗肿瘤功效。本项目有望揭示老药碳酸锂抗肿瘤作用的免疫学机理和途径，开发以固有免疫为基础的抗肿瘤免疫新疗法。

Cancer Immunotherapy that lies on innate immune responses has not been well established yet. Macrophages play critical roles in innate immune system. Although macrophages are capable of killing tumor cells, typically for so-called M1 macrophages, they are commonly educated into M2 macrophages, which promote tumor angiogenesis, tumor escaping and metastasis. Targeting these M2 macrophages holds great potential in cancer immunotherapy. Previous studies have revealed that there are some obvious differences between M1 and M2 macrophages in metabolic mode. Our investigations also indicated that M1 phenotype is regulated by glycolysis pathway. Increased glycolysis may contribute to the reprogramming of M2 to M1 phenotype. Based on the above findings, we hypothesize that lithium carbonate which is a classical inhibitor of GSK-3βcould reeducate M2 tumor-promoting macrophages into M1 tumor-inhibiting macrophages by restoring Gys1 activity and increasing glycogen synthesis. We aim to investigate the effects of lithium carbonate on macrophage polarization, bioactivity and the underlying mechanisms. We will also investigate how lithium carbonate ameliorates tumor immune microenvironment and suppress tumor growth by reeducating M2 macrophages. This project will reveal the anti-tumor immune responses and mechanisms of lithium carbonate, and pave the way for tumor immunotherapy utilizing innate immune system.