Researchers in South Korea have identified a mitochondrial metabolic checkpoint that controls macrophage trained immunity and enhances tumor control in mice, according to a peer-reviewed study published in Nature Communications. The study, led by Jung Min Han at Yonsei University, found that restricting mitochondrial glutamine transport programs innate immune cells to sustain memory-like responses.
Using integrated transcriptomic, metabolomic, and epigenomic profiling, the researchers demonstrated that TLR4-NF-κB signaling represses SLC1A5_var, a mitochondrial glutamine transporter. This repression limits glutaminolysis and reduces the availability of α-ketoglutarate. The resulting metabolic restriction prevents the demethylase KDM5B from removing the activating histone mark histone H3 lysine 4 trimethylation, which maintains inflammatory gene accessibility during lipopolysaccharide-induced training.
In murine cancer models, pharmacological inhibition or myeloid-specific knockdown of SLC1A5_var strengthened macrophage training and improved tumor control. Conversely, enforcing SLC1A5_var expression or providing α-ketoglutarate supplementation abrogated those antitumor effects, establishing an SLC1A5_var-α-ketoglutarate-KDM5B metabolic-epigenetic axis.
The work included collaborators from Yonsei University, Chung-Ang University, and the Yonsei-SL Bigen Research Institute. Funding was provided by the National Research Foundation of Korea and the Korea Drug Development Fund under South Korea's Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare. The paper was submitted on December 11, 2025, accepted on August 3, 2026, and published on August 15, 2026.
