Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice

Abstract

Trained immunity enables innate immune cells to acquire memory-like responses, offering a strategy to enhance antitumor immunity. However, the metabolic‒epigenetic mechanisms underlying this process remain poorly defined. Here, we show that lipopolysaccharide-induced macrophage training is encoded by a mitochondrial metabolic checkpoint. Integrated transcriptomic, metabolomic, and epigenomic profiling reveals that TLR4-NF-κB signaling represses SLC1A5_var, a mitochondrial glutamine transporter, limiting glutaminolysis and reducing α-ketoglutarate availability. This metabolic restriction limits removal of the activating histone mark histone H3 lysine 4 trimethylation by KDM5B, thereby maintaining inflammatory gene accessibility. Functionally, pharmacological inhibition or myeloid-specific knockdown of SLC1A5_var potentiates macrophage training and improves tumor control in murine cancer models, whereas enforced SLC1A5_var expression or α-ketoglutarate supplementation abrogates these effects. These findings define an SLC1A5_var-α-ketoglutarate-KDM5B metabolic-epigenetic axis that programs macrophage trained immunity and illustrate how targeted metabolic restriction can be leveraged to enhance innate immune responses against cancer. Trained immunity results in improved secondary response to stimulus in innate immune cells. Here the authors show that trained immunity in macrophages establishes a mitochondrial glutamine-restriction metabolic checkpoint and explore its role in a murine model of tumor immunity.