犬尿氨酸上调巨噬细胞MS4A4A促进结直肠癌免疫逃逸的分子机制

肿瘤的发生、发展是与免疫微环境相互博弈的结果。肿瘤细胞与免疫细胞间的代谢竞争及代谢产物相互作用是促使肿瘤免疫逃逸的重要因素，但结直肠癌细胞通过代谢产物调控肿瘤相关巨噬细胞（TAM）的机制尚未阐明。我们预实验结果发现，结直肠癌细胞分泌的犬尿氨酸，可能通过激活TAM中AHR-KLF4通路，上调MS4A4A的表达，继而促使TAM向M2型极化，并导致T细胞耗竭。因此我们提出肿瘤细胞代谢产物犬尿氨酸上调TAM中MS4A4A促结直肠癌免疫逃逸的科学假说。本项目拟：1.阐明MS4A4A调控TAM极化及免疫微环境促结直肠癌免疫逃逸的作用及机制；2.揭示犬尿氨酸激活TAM中AHR-KLF4通路调控MS4A4A表达的分子机制；3.探讨阻断MS4A4A在结直肠癌免疫治疗的作用。本研究着眼于探寻TAM极化的关键环节，旨在揭示肿瘤代谢重塑免疫微环境的新机制，为结直肠癌预后判断及免疫治疗提供新的靶点和策略。

The occurrence and development of tumors are the result of competition with the immune microenvironment. Metabolic competition and metabolite interactions between tumor cells and immune cells are important factors that promote tumor immune escape, but the mechanism by which colorectal cancer (CRC) cells regulate tumor-associated macrophages (TAM) through metabolites has not been elucidated. Our previous work found that kynurenine secreted by CRC cells could regulate the expression of Membrane Spanning 4-Domains A4A (MS4A4A) in TAM through AHR-KLF4 pathway, which led to macrophages M2 polarization and caused T cell exhaustion. Based on our preliminary results, we hypothesize that kynurenine, as a metabolite of tumor cells, could promote immune escape of CRC via up-regulating MS4A4A expression in TAM. To verify this hypothesis, firstly, we will further clarify the function and mechanism of MS4A4A in regulating TAM polarization and immune microenvironment to promote immune escape of CRC. Secondly, we will elucidate the molecular mechanism by which kynurenine activates the AHR-KLF4 pathway in TAM to regulate the expression of MS4A4A. Finally, we will explore the effect of blocking MS4A4A in immunotherapy of CRC. This study focuses on exploring the key aspects of TAM polarization, and aims to reveal new mechanisms of tumor metabolism remodeling the immune microenvironment, and provides new targets and strategies for prognosis and immunotherapy of CRC.