近日，南方医科大学石敏、廖旺军研究团队揭示，巨噬细胞和成纤维细胞之间的烟酰胺代谢对抗操纵胃癌的微环境。2024年6月18日，国际知名学术期刊《细胞—代谢》发表了这一成果。

通过转录组学分析和动态血浆样本分析，课题组人员确定了肿瘤微环境中的代谢“对抗”机制，如烟酰胺代谢的双重预后意义。具体来说，巨噬细胞和成纤维细胞分别表达限速酶烟酰胺磷酸核糖基转移酶和烟酰胺N-甲基转移酶，调节烟酰胺/1-甲基烟酰胺比例和CD8⁺ T细胞功能。

机制上，烟酰胺N-甲基转移酶被NOTCH通路转录因子RBP-J转录激活，并通过SIRT1/NICD轴被含有烟酰胺磷酸化核糖基转移酶的，巨噬细胞来源的细胞外囊泡进一步抑制。通过细胞外囊泡注入自身调节烟酰胺代谢，可恢复胃癌中CD8⁺T细胞的细胞毒性和抗PD-1反应。

据了解，免疫检查点阻断使晚期胃癌治疗取得突破。然而，胃癌中突出的异质性，特别是肿瘤微环境的异质性，强调了抗肿瘤反应是多因子相互作用的反映。

附：英文原文

Title: Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer

Author: Yu Jiang, Yawen Wang, Guofeng Chen, Fei Sun, Qijing Wu, Qiong Huang, Dongqiang Zeng, Wenjun Qiu, Jiao Wang, Zhiqi Yao, Bishan Liang, Shaowei Li, Jianhua Wu, Na Huang, Yuanyuan Wang, Jingsong Chen, Xiaohui Zhai, Li Huang, Beibei Xu, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Wangjun Liao, Min Shi

Issue&Volume: 2024-06-18

Abstract: Immune checkpoint blockade has led to breakthroughs in the treatment of advanced gastric cancer. However, the prominent heterogeneity in gastric cancer, notably the heterogeneity of the tumor microenvironment, highlights the idea that the antitumor response is a reflection of multifactorial interactions. Through transcriptomic analysis and dynamic plasma sample analysis, we identified a metabolic “face-off” mechanism within the tumor microenvironment, as shown by the dual prognostic significance of nicotinamide metabolism. Specifically, macrophages and fibroblasts expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase and nicotinamide N-methyltransferase, respectively, regulate the nicotinamide/1-methylnicotinamide ratio and CD8+ T cell function. Mechanistically, nicotinamide N-methyltransferase is transcriptionally activated by the NOTCH pathway transcription factor RBP-J and is further inhibited by macrophage-derived extracellular vesicles containing nicotinamide phosphoribosyltransferase via the SIRT1/NICD axis. Manipulating nicotinamide metabolism through autologous injection of extracellular vesicles restored CD8+ T cell cytotoxicity and the anti-PD-1 response in gastric cancer.

DOI: 10.1016/j.cmet.2024.05.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00189-X