肿瘤相关巨噬细胞（TAM）在肝癌进展中具有双重作用--促炎的M1型TAM抑制肿瘤而抑炎的M2型TAM促进肿瘤。申请人曾首次报道肝癌中存在促炎的M2型（CD206+IL-1β+）TAM，且IL-1β促进肝癌上皮间质转化和转移。但该群TAM在肝癌中发挥促炎功能的调控机制尚不清楚。初步研究发现肝癌微环境中脂肪酸增多，脂肪酸氧化促进M2型TAM分泌IL-1β，且琥珀酸脱氢酶（SDH）发挥关键作用。我们据此猜测：HCC中高脂肪酸微环境促进CD206+IL-1β+ TAM脂肪酸氧化，通过代谢重编程增加SDH活性，促进IL-1β分泌和肝癌进展。本课题拟从"癌细胞-微环境-TAM"角度明确癌细胞对TAM的代谢调控作用，从SDH活性角度阐明脂肪酸氧化调节TAM IL-1β分泌的分子机制。本研究将从代谢调控这一全新角度探讨肝癌"驯化"TAM促癌机制，丰富"炎-癌"理论，有助于开发肝癌治疗新方法。

Tumor-associated macrophage (TAM) has a dual-role in the progression of hepatocellular carcinoma (HCC). Traditional understanding is that pro-inflammatory M1-type TAM inhibits tumor progression while anti-inflammatory M2-type TAM promotes tumor progression. The applicant previously revealed a subtype of pro-inflammatory M2-type (CD206+IL-1β+) TAM, and proved that IL-1β induces HCC cells undergo epithelial-to-mesenchymal transition and HCC progression. However, it is unknown how the pro-inflammatory function of this TAM subtype is regulated. Our preliminary findings showed that free fatty acid level was increased in HCC microenvironment, and that fatty acid oxidation facilitated IL-1β secretion of HCC-related M2-type TAMs. Succinate dehydrogenase (SDH) was found to be critical in this process. We thus hypothesize that the increased fatty acid in HCC microenvironment can promote fatty acid oxidation and enhance SDH activity by a metabolic reprogramming manner in CD206+IL-1β+ TAMs, leading to IL-1β secretion and HCC progression. In this study, we will use materials including but not limited to human tissue, induced pluripotent cells, and genetic engineering mouse models to confirm the effects of metabolically reprogrammed TAMs by HCC cells through a "tumor cell-microenvironment-TAM" view. In addition, we hope to uncover the molecular mechanisms by which fatty acid oxidation regulates IL-1β secretion of TAMs from an SDH view. Our project will explore the way of HCC educate TAM from a novel perspective, which can contribute to deeper understanding of the "tumor-inflammation" theory and may be helpful for the development of novel strategies for HCC treatment.