Open Access

REVIEW

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

Dongchi Cai^1,2,#, Jialin Ji^3,#, Chunhui Yang^1,*, Hong Cai^1,*

1 Department of Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian, 116023, China
2 Department of Clinical Laboratory, Anshan Central Hospital, Anshan, 114000, China
3 Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116021, China

* Corresponding Authors: Chunhui Yang. Email: ; Hong Cai. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: Targeting the Tumor Microenvironment: Emerging Insights into Cancer Progression and Therapeutics)

Oncology Research 2026, 34(1), . https://doi.org/10.32604/or.2025.071152

Received 01 August 2025; Accepted 31 October 2025; Issue published 30 December 2025

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.

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Keywords

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