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

Regulatory T (Treg) cells prevent autoimmune diseases but limit antitumor immunity. Tumor‑infiltrating Treg (Ti‑Treg) cells exhibit metabolic traits as potential antitumor targets. Here, we find that Ti-Treg cells upregulate glutamate dehydrogenase 1 (GDH1), increasing α-ketoglutarate (α-KG) levels. Elevated GDH1 in Ti-Treg cells accelerates tumor progression. Mechanistically, in a lactate rich microenvironment, GDH1 lactylation boosts α-KG production to fuel ALKBH5-mediated Wnt2 expression in Ti-Treg cells. Enhanced WNT2 promotes natural killer (NK) cell senescence. GDH1 inhibition or SLC16A1 deletion in Ti-Treg cells reduces NK senescence and improves adoptive NK transfer therapy. We reveal a lactate-α‑KG metabolic circuit driving NK senescence, offering therapeutic targets to boost antitumor immunity.