精胺合成酶SMS通过调控巨噬细胞募集与M2型极化介导肝癌免疫逃逸的分子机制

肿瘤细胞与免疫细胞间的代谢竞争及代谢产物的相互作用是促使免疫抑制微环境形成的关键因素，但肝癌细胞通过代谢产物重塑免疫微环境的机制尚未阐明。我们预实验结果发现，精胺合成酶（SMS）在肝癌中高表达，并促进其代谢产物精胺的大量合成，进入肿瘤微环境的精胺通过活化巨噬细胞内AKT-CSF1信号通路而诱导肿瘤相关巨噬细胞（TAM）的募集及M2型极化。基于前期工作基础，我们提出SMS通过其代谢产物精胺塑造免疫抑制微环境，继而介导肝癌免疫逃逸的科学假说。本研究拟：1.揭示SMS通过其代谢产物精胺活化AKT-CSF1信号调控TAM的功能及机制；2.阐明SMS-精胺重塑免疫微环境调控肝癌免疫逃逸的分子机制；3.探讨阻断精胺合成与转运在肝癌免疫治疗中的作用；并结合临床样本，探讨SMS/精胺对肝癌预后及免疫治疗疗效的预测价值。本研究旨在揭示肝癌免疫逃逸的新机制，为肝癌预后判断及免疫治疗提供新的靶点和策略。

The metabolic interaction between cancer cells and immune cells is an important factor for the formation of the immunosuppressive microenvironment, but how the metabolic reprogramming of hepatocellular carcinoma (HCC) cells changes and reshapes the immune microenvironment has not yet been elucidated. In our previous work, we found that spermine synthase (SMS) was significantly upregulated in HCC cells and led to huge synthesis of its metabolite spermine. Spermine can induce tumor-associated macrophages (TAM) recruitment and M2-type polarization via AKT/CSF1 signaling pathway. Based on our preliminary results, we hypothesize that SMS-mediated spermine synthesis could reshape the immunosuppressive microenvironment and lead to the immune escape of HCC. In this study, we will firstly elucidate the mechanism of SMS in regulating TAM through AKT-CSF1 signal via its metabolic products-spermine. Secondly, we will explore the mechanisms of SMS-spermine in reshaping the immune microenvironment that lead to immune escape of HCC. Thirdly, we will further try to figure out whether blocking spermine synthesis and transport could sensitize the effect of immunotherapy in HCC and explore the potential of SMS or spermine as a biomarker of the prognosis of HCC patients and the efficacy of immunotherapy with clinical samples. Our study aims to reveal new mechanisms of immune escape in HCC and provide new targets and strategies for prognosis and treatment of HCC.