Nicotinamide is the amide compound of niacin. It is a white crystalline powder; odorless or almost odorless, bitter in taste; slightly hygroscopic. Nicotinamide is easily soluble in water or ethanol, soluble in glycerol. It mainly exists in nature in cereal husks, yeast, peanuts, meat, animal organs, milk and green leafy vegetables. It can be synthesized from tryptophan in the human body, but the efficiency is extremely low. Escherichia coli and other bacteria in the intestine can synthesize niacin and then convert it into nicotinamide.
Nicotinamide is a component of coenzyme I and coenzyme II and serves as a coenzyme for many dehydrogenases. When lacking, it can affect the normal respiration and metabolism of cells and cause pellagra. Nicotinamide is easily absorbed from the gastrointestinal tract and is distributed to tissues throughout the body after absorption. It is metabolized by the liver and only a small amount is excreted in the urine in its original form.
The tumor microenvironment (TME) of gastric cancer has significant heterogeneity, and the efficacy of immune checkpoint blockade (ICB) is the dynamic result of the face-off game between multiple components of the TME. On the one hand, there are complex interactions between the naturally formed "anti-tumor" and "pro-tumor" cell camps in the TME; on the other hand, the multidirectional flow of metabolites between cells further aggravates the changes in the TME. However, the complexity of metabolic networks brings great challenges to the comprehensive assessment of the immune microenvironment of gastric cancer. The discovery of the unique nicotinamide "metabolic game" phenomenon in the immune microenvironment of gastric cancer provides research directions for revealing the heterogeneity of the immune microenvironment of gastric cancer and new metabolic targets.
The researchers first used metabolite activity scores and prognostic analysis and found that the scores of the metabolites nicotinamide (NAM) and methylnicotinamide (MNAM) had opposite prognostic values in the gastric cancer cohort. In addition, in plasma samples of patients with gastric cancer, non-small cell lung cancer, and esophageal cancer before and after receiving ICB treatment, it was found that the level of NAM/MNAM ratio in patients who responded to treatment was significantly higher than that in patients who did not respond, and it changed dynamically with the efficacy.
Subsequently, the researchers found that NAMPT and NNMT, two rate-limiting enzymes in nicotinamide metabolism, were specifically expressed in macrophages and fibroblasts, respectively, and induced TME associated with immune activation and immune suppression, respectively. So, how do macrophages and fibroblasts exert immune regulation through nicotinamide metabolism? The authors further confirmed that NNMT-expressing fibroblasts secrete the metabolite MNAM, which inhibits T cell cytotoxicity by reducing IκB phosphorylation and NF-κB activation. On the other hand, macrophages can secrete NAMPT-containing extracellular vesicles (EVs), which serve as a "bridge" for metabolic interactions between cells, significantly inhibiting the expression of NNMT in fibroblasts in the co-culture system, and unfolding nicotinamide metabolic crosstalk.
In addition, the researchers explored the specific mechanism of nicotinamide metabolic crosstalk. Combining pathway enrichment, JASPAR database screening, ChIP and dual-luciferase reporter gene experiments, the researchers confirmed that the NOTCH pathway transcription factor RBP-J can bind to the NNMT promoter, thereby activating NNMT transcription. In addition, macrophage-derived EVs can mediate deacetylation of the intracellular segment NICD of NOTCH ligand through SIRT1, inhibiting NOTCH signaling and NNMT expression in fibroblasts. Finally, in vivo experiments show that autologous reinfusion of NAMPT-containing EVs derived from macrophages can enhance the toxicity of CD8+ T cells and sensitize the ICB therapeutic response in gastric cancer mice, demonstrating the potential of targeting nicotinamide metabolism combined with anti-PD-1 in the treatment of gastric cancer.
In summary, this study found that macrophages and fibroblasts act as "players" in the nicotinamide "metabolic game" in the TME of gastric cancer, dynamically regulating the function of CD8+ T cells and identifying the key bridge that drives the game - EVs containing NAMPT. The study revealed a special metabolic crosstalk phenomenon in the heterogeneous microenvironment of gastric cancer, highlighted the potential and application prospects of nicotinamide metabolites as ICB efficacy markers, and proposed that targeting NAMPT-EV can be used as an immune combination therapy.
