Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer.
Cell Metab
; 36(8): 1806-1822.e11, 2024 Aug 06.
Article
in En
| MEDLINE
| ID: mdl-38897198
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stomach Neoplasms
/
Niacinamide
/
Nicotinamide Phosphoribosyltransferase
/
Tumor Microenvironment
/
Macrophages
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Cell Metab
Journal subject:
METABOLISMO
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United States