Increases in 4‐Acetaminobutyric Acid Generated by Phosphomevalonate Kinase Suppress CD8+ T Cell Activation and Allow Tumor Immune Escape

Abstract Certain metabolites in the tumor microenvironment (TME) can alter innate immunity. Here, it is shown how phosphomevalonate kinase (PMVK) allows hepatocellular carcinoma (HCC) cells to overcome the anti‐tumor immunity mediated by CD8 + T cells. In HCCs, depletion of PMVK is required to facilitate CD8 + T cell activation and their subsequent suppression of tumor growth. Mechanistically, PMVK phosphorylates and stabilizes glutamate decarboxylase 1 (GAD1), thus increasing the synthesis of γ‐aminobutyric acid (GABA), which normally functions as a neurotransmitter. However, PMVK also recruits acetyl‐CoA acetyltransferase 1 (ACAT1) and allows it to convert GABA, to 4‐acetaminobutyric acid (4‐Ac‐GABA), which is released into the TME. There, 4‐Ac‐GABA activates the GABAA receptor (GABAAR) on CD8 + T cells, which inhibits AKT1 signaling. This in turn suppresses CD8 + T cell activation, intratumoral infiltration, and the anti‐tumor response. Inhibiting PMVK or GABAAR in HCC mouse models overcomes resistance to anti‐PD‐1 immune checkpoint therapy. These findings reveal non‐canonical and cooperative functions among the key metabolic enzymes PMVK, GAD1, and ACAT1 that reprogram glutamine metabolism to synthesize a potent CD8 + T cell inhibitor 4‐Ac‐GABA. Blocking 4‐Ac‐GABA signaling in CD8 + T cells, particularly when combined with immune checkpoint inhibition, potentially represents a new and potent form of immunotherapy.