Aging microenvironment induces CD8(+) T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.

Aging reduces hepatic β-hydroxybutyrate synthesis, inducing CD8(+) T cell exhaustion and impairing antiviral and antitumor immunity in mice.

• Why it matters: Understanding how aging affects T cell function is crucial for improving immunotherapy outcomes in older individuals, as the mechanisms behind immunosenescence are not fully known.
• What they did: The study used metabolic analysis, genetic ablation of hepatic BDH1, and 3HB supplementation in mice to investigate the role of β-hydroxybutyrate in T cell exhaustion, identifying PRKAR1B as a key effector.
• The result: 3HB supplementation reverses T cell exhaustion and restores CAR T cell antitumor activity, suggesting 3HB as a potential strategy to enhance immune responses in aged populations.