De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function

• Published in: Cell reports (Cambridge) 2023-12, Vol.42 (12), p.113518-113518, Article 113518
• Main Authors: Wan, Jie, Cheng, Cheng, Hu, Jiajia, Huang, Haiyan, Han, Qiaoqiao, Jie, Zuliang, Zou, Qiang, Shi, Jian-Hong, Yu, Xiaoyan
• Format: Article
• Language: English
• Subjects: CD8-Positive T-Lymphocytes - metabolism; CP: Cancer; CP: Metabolism; Humans; Kynurenine - metabolism; Metabolic Networks and Pathways; NAD - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113518

The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function. [Display omitted] •KP-derived NAD+ is involved in antitumor CD8+ T cell responses•De novo NAD+ synthesis promotes glycolysis and oxidative phosphorylation•De novo NAD+ generation restrains PTEN-dependent metabolic defects•Impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in CRC How the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Wan et al. reveal that de novo NAD+ synthesis is involved in CD8+ T cell metabolic programming and antitumor function, suggesting that modulation of de novo NAD+ synthesis could restore CD8+ T cell antitumor activity.