From Amino Acid Sensing to Amino Acid Metabolism and Beyond:
Metabolic Logic of Cancer, Immunity, and Drug Discovery
Jung Min Han
College of Pharmacy, Yonsei University, South Korea
Cells interpret nutrient availability not merely as a source of energy or biomass, but as fundamental biological information that governs protein synthesis, growth, survival, adaptation, and cell fate. Among nutrients, amino acids occupy a unique position as both metabolic substrates and signaling molecules, linking environmental cues to cellular signaling, mitochondrial function, epigenetic regulation, and immune responses.
In this seminar, I will trace our research journey from amino acid sensing to amino acid metabolism and beyond, while also introducing our recent findings and ongoing research programs. Our early studies identified leucyl-tRNA synthetase (LARS1) as a leucine sensor that connects amino acid availability to mTORC1 signaling, revealing that enzymes classically associated with protein synthesis can also function as nutrient-responsive signaling regulators. Extending this concept to cancer metabolism, we discovered and characterized a mitochondrial glutamine transporter variant, SLC1A5_var, which enables cancer cells to sustain mitochondrial glutamine metabolism, TCA cycle activity, redox homeostasis, and survival. Through the development of a first-in-class inhibitor targeting this pathway, we further demonstrated that mitochondrial glutamine transport represents an actionable metabolic vulnerability in cancer.
I will then discuss our recent studies showing that mitochondrial glutamine metabolism also serves as a metabolic checkpoint in immune regulation. In macrophage trained immunity, suppression of mitochondrial glutamine transport rewires α-ketoglutarate–dependent chromatin remodeling and enhances durable antitumor innate immune memory. These findings suggest that amino acid metabolism is not only a cancer cell-intrinsic dependency, but also a regulatory axis that shapes immune function within the tumor microenvironment.
Finally, I will introduce our current and emerging research directions that expand these mechanistic insights into new areas of cancer biology, immunometabolism, and therapeutic discovery. These include ongoing studies on nutrient signaling, metabolic adaptation, epigenetic memory, tumor–immune interactions, and AI-driven drug discovery platforms that integrate generative molecular design with automated synthesis. By combining mechanistic biochemistry, isotope tracing, chemical biology, animal models, and computational approaches, our recent and ongoing work aims to translate the metabolic logic of amino acid regulation into precision therapeutic opportunities.
Together, these studies illustrate how decoding amino acid sensing and metabolism can reveal fundamental principles of life and disease. This seminar will highlight how amino acid metabolism serves as a causal node connecting nutrient information, mitochondrial metabolism, chromatin regulation, immune memory, and therapeutic vulnerability, opening new avenues for cancer metabolism, immunometabolism, and drug discovery.
