A lactate-α-ketoglutarate metabolic circuit in tumor-infiltrating regulatory T cells accelerates tumor progression by inducing NK cell senescence.

Lactate-α-ketoglutarate metabolic circuit in tumor-infiltrating Treg cells promotes tumor progression by inducing NK cell senescence, with GDH1 as a key driver.

• Why it matters: Understanding how Treg cells suppress antitumor immunity is crucial for developing effective cancer therapies, especially since their metabolic traits can be targeted to enhance immune responses.
• What they did: The study examined tumor-infiltrating Treg cells, revealing that upregulation of GDH1 increases α-ketoglutarate levels through lactylation in a lactate-rich environment, which promotes Wnt2 expression and NK cell senescence.
• The result: Inhibiting GDH1 or SLC16A1 reduces NK cell senescence and enhances adoptive NK cell therapy, highlighting a metabolic pathway that can be targeted to improve antitumor immune responses.