Branched-Chain Amino Acid Metabolic Reprogramming and Cancer: Molecular Mechanisms, Immune Regulation, and Precision Targeting.

Abstract

Metabolic reprogramming involving branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine-is increasingly recognized as pivotal in cancer progression, metastasis, and immune modulation. This review comprehensively explores how cancer cells rewire BCAA metabolism to enhance proliferation, survival, and therapy resistance. Tumors manipulate BCAA uptake and catabolism via high expression of transporters like L-type amino acid transporter 1 (LAT1) and enzymes including branched chain amino acid transaminase 1(BCAT1), branched chain amino acid transaminase 2 (BCAT2), branched-chain alpha-keto acid dehydrogenase (BCKDH), and branched chain alpha-keto acid dehydrogenase kinase (BCKDK). These alterations sustain energy production, biosynthesis, redox homeostasis, and oncogenic signaling (especially mammalian target of rapamycin complex 1 [mTORC1]). Crucially, tumor-driven BCAA depletion also shapes an immunosuppressive microenvironment, impairing anti-tumor immunity by limiting essential nutrients for T cells and natural killer (NK) cells. Innovative therapeutic strategies targeting BCAA pathways-ranging from selective small-molecule inhibitors (e.g., LAT1 and BCAT1/2) to dietary modulation-have shown promising preclinical and early clinical efficacy, highlighting their potential to exploit metabolic vulnerabilities in cancer cells while bolstering immune responses. By integrating multi-omics data and precision targeting approaches, this review underscores the translational significance of BCAA metabolic reprogramming, positioning it as a novel frontier in cancer treatment.