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L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review)

  • Authors:
    • Xiaoqing Zheng
    • Jianji Pan
    • Donghai Lin
    • Wei Shao
  • View Affiliations / Copyright

    Affiliations: Precision Medicine Application and Transformation Central Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361000, P.R. China, High Field NMR Center, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361000, P.R. China, Precision Medicine Application and Transformation Central Laboratory, Xiamen Humanity Hospital, Fujian Medical University, Xiamen, Fujian 361000, P.R. China
    Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 170
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    Published online on: August 19, 2025
       https://doi.org/10.3892/ijmm.2025.5611
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Abstract

L‑type amino acid transporter 1 (LAT1) has emerged as a critical molecular target for advancing boron neutron capture therapy (BNCT), a promising treatment that leverages selective boron accumulation and neutron irradiation to eradicate cancer cells. The frequent upregulation of LAT1 in aggressive tumors (such as gliomas and specific subtypes of lung and breast cancer) underpins its essential role as the principal mediator of tumor‑selective boron compound uptake in BNCT. The present review comprehensively examines the structure and function of LAT1, the mechanistic principles of boron transport (including LAT1 mediation) and the key regulatory pathways governing BNCT efficacy. Building on this and given the role of LAT1 in reprogramming tumor metabolism through amino acid transport, advanced metabolomics tools, particularly liquid chromatography‑mass spectrometry and nuclear magnetic resonance, offer a novel approach for clarifying the contribution of LAT1 to BNCT. These techniques hold significant potential to map metabolic profiles altered by LAT1‑mediated boron compound uptake, thereby elucidating downstream biochemical consequences relevant to the therapeutic efficacy and resistance mechanisms. Synthesizing the dual role of LAT1 as both a vulnerability and therapeutic target in BNCT, the present review systematizes key challenges, including the need for selective boron compounds, resistance mechanisms and off‑target effects, while mapping actionable pathways to unlock its potential via refined regulation strategies, next‑generation delivery agents and personalized approaches. By addressing these knowledge gaps, this synthesis provides a foundational framework to harness LAT1‑targeted BNCT, offering potential to advance precision oncology paradigms and improve clinical outcomes for patients with LAT1‑enriched tumors.
View Figures

Figure 1

Schematic representation of the
therapeutic principle of BNCT and the specific uptake of
boron-containing compounds by LAT1 in the TME. (A) During
epithermal neutron irradiation, 10B selectively
accumulated in tumor cells undergo the neutron capture reaction,
producing high-LET α-particles (4He) and lithium ions
(7Li) that induce complex DNA double-strand breaks.
LAT1-targeted strategies enhance the selective accumulation of
10B-containing compounds in tumor cells, highlighting
its role in BNCT efficacy. (B) Novel boron-containing compounds
with structural similarity to Tyr, such as BPA, are transported
into the cell through LAT1 on the cell membrane, leading to an
increase in the concentration of 10B-containing
compounds in cancer cells. The oncogene c-Myc binds to the LAT1
promoter, which promotes LAT1 transcription and expression in the
nucleus. In addition, the CD133 promoter can also promote LAT1
upregulation. Together they improve the TME. LAT1, L-type amino
acid transporter 1; BNCT, boron neutron capture therapy; TME, tumor
microenvironment; LET, linear energy transfer; BPA,
boronophenylalanine; BTS, 3-borono-L-tyrosine;
[18F]FBPA, 18F-fluoro-borono-phenylalanine;
HIF-α, hypoxia-inducible factor-α.

Figure 2

Schematic representation of the
structure and functional mechanisms of LAT1. LAT1 forms a
functional heterodimer with 4F2hc at the plasma membrane,
covalently linked by disulfide bonds. This complex facilitates the
transport of essential amino acids such as Leu, Trp, Met and Gln
into the cell. The accumulated amino acids activate the mTOR
pathway, leading to the phosphorylation of the translation
regulators p70S6K and 4E-BP1. This activation also inhibits
autophagy and promotes tumor cell proliferation via the PI3K
pathway. In addition, upregulating the expression of LAT1 could
activate integrin signaling pathways, including p130CAS/FAK. This
signaling promotes tumor cell survival, anchorage independence and
metastasis, highlighting the central role of LAT1 in cancer
progression. LAT1, L-type amino acid transporter 1; p70S6K, p70 S6
kinase; 4E-BP1, eukaryotic translation initiation factor 4E-binding
protein 1; PI3K, phosphatidylinositol 3-kinase; p130CAS, p130
Crk-associated substrate; FAK, focal adhesion kinase.

Figure 3

Application of metabolomics in BNCT.
LAT1 facilitates amino acid transport and contributes to the
formation of a distinct tumor metabolic microenvironment. BNCT uses
LAT1 to promote the selective accumulation of boron-containing
compounds in tumor cells, thereby inducing metabolic changes within
the tumor microenvironment. Metabolomics techniques such as NMR and
LC-MS enable comprehensive profiling of metabolic pathways in
tumors, providing critical insights that can guide physicians in
developing more effective and safer BNCT treatment strategies.
LAT1, L-type amino acid transporter 1; BNCT, boron neutron capture
therapy; LC-MS, liquid chromatography-mass spectrometry; NMR,
nuclear magnetic resonance.
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Zheng X, Pan J, Lin D and Shao W: L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review). Int J Mol Med 56: 170, 2025.
APA
Zheng, X., Pan, J., Lin, D., & Shao, W. (2025). L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review). International Journal of Molecular Medicine, 56, 170. https://doi.org/10.3892/ijmm.2025.5611
MLA
Zheng, X., Pan, J., Lin, D., Shao, W."L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review)". International Journal of Molecular Medicine 56.5 (2025): 170.
Chicago
Zheng, X., Pan, J., Lin, D., Shao, W."L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 170. https://doi.org/10.3892/ijmm.2025.5611
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Spandidos Publications style
Zheng X, Pan J, Lin D and Shao W: L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review). Int J Mol Med 56: 170, 2025.
APA
Zheng, X., Pan, J., Lin, D., & Shao, W. (2025). L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review). International Journal of Molecular Medicine, 56, 170. https://doi.org/10.3892/ijmm.2025.5611
MLA
Zheng, X., Pan, J., Lin, D., Shao, W."L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review)". International Journal of Molecular Medicine 56.5 (2025): 170.
Chicago
Zheng, X., Pan, J., Lin, D., Shao, W."L‑type amino acid transporter 1 in enhancing boron neutron capture therapy: Mechanisms, challenges and future directions (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 170. https://doi.org/10.3892/ijmm.2025.5611
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