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

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

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.