Yajie Zhao, Chunrui Pu, Kangdong Liu, Zhenzhen Liu
{"title":"Targeting LAT1 with JPH203 to reduce TNBC proliferation and reshape suppressive immune microenvironment by blocking essential amino acid uptake","authors":"Yajie Zhao, Chunrui Pu, Kangdong Liu, Zhenzhen Liu","doi":"10.1007/s00726-025-03456-3","DOIUrl":null,"url":null,"abstract":"<div><p>The competitive uptake of essential amino acids (EAAs) by breast cancer cells is associated with poor patient prognosis and the development of an immunosuppressive tumor microenvironment. L-type amino acid transporters, LAT1 (<i>SLC7 A5</i>) and LAT2 (<i>SLC7 A8</i>) are major mediators of EAAs transmembrane uptake and are overexpressed in some tumor tissues. However, the distribution and functional roles of these transporters across breast cancer subtypes have not been fully elucidated. This study aims to investigate the therapeutic potential of targeting EAA transporters, particularly LAT1, in triple-negative breast cancer (TNBC) and its role in remodeling the tumor immune microenvironment. The distribution of EAA transporters across breast cancer subtypes was analyzed using multi-omics data. The effects of LAT1 targeting on TNBC cell proliferation and EAA uptake were evaluated using <i>SLC7 A5</i> knockout and LAT1 inhibitors in vitro experiments. A 4T1-BALB/c tumor-bearing mouse model with normal immune function was constructed to investigate the effects of LAT1 targeting on tumor growth and immune microenvironment remodeling in vivo. TNBC demonstrated a strong dependence on LAT1-mediated EAAs uptake. Targeting LAT1 limited the exogenous supply of EAAs, leading to amino acid starvation, cell cycle arrest, and increased apoptosis in TNBC cells. The in vivo experiments, using a 4T1-BALB/c tumor-bearing mouse model, showed that LAT1 targeting inhibited tumor growth and remodeled the immunosuppressive tumor microenvironment. Targeting LAT1 improved PD-L1-associated immune suppression and improved the efficacy of PD-1 antibody treatment, producing synergistic anti-tumor effects. This study highlights the therapeutic potential of targeting LAT1 in TNBC, particularly in remodeling the tumor immune microenvironment. The findings provide a promising strategy for immune combination therapy in TNBC.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":7810,"journal":{"name":"Amino Acids","volume":"57 1","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00726-025-03456-3.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Amino Acids","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s00726-025-03456-3","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The competitive uptake of essential amino acids (EAAs) by breast cancer cells is associated with poor patient prognosis and the development of an immunosuppressive tumor microenvironment. L-type amino acid transporters, LAT1 (SLC7 A5) and LAT2 (SLC7 A8) are major mediators of EAAs transmembrane uptake and are overexpressed in some tumor tissues. However, the distribution and functional roles of these transporters across breast cancer subtypes have not been fully elucidated. This study aims to investigate the therapeutic potential of targeting EAA transporters, particularly LAT1, in triple-negative breast cancer (TNBC) and its role in remodeling the tumor immune microenvironment. The distribution of EAA transporters across breast cancer subtypes was analyzed using multi-omics data. The effects of LAT1 targeting on TNBC cell proliferation and EAA uptake were evaluated using SLC7 A5 knockout and LAT1 inhibitors in vitro experiments. A 4T1-BALB/c tumor-bearing mouse model with normal immune function was constructed to investigate the effects of LAT1 targeting on tumor growth and immune microenvironment remodeling in vivo. TNBC demonstrated a strong dependence on LAT1-mediated EAAs uptake. Targeting LAT1 limited the exogenous supply of EAAs, leading to amino acid starvation, cell cycle arrest, and increased apoptosis in TNBC cells. The in vivo experiments, using a 4T1-BALB/c tumor-bearing mouse model, showed that LAT1 targeting inhibited tumor growth and remodeled the immunosuppressive tumor microenvironment. Targeting LAT1 improved PD-L1-associated immune suppression and improved the efficacy of PD-1 antibody treatment, producing synergistic anti-tumor effects. This study highlights the therapeutic potential of targeting LAT1 in TNBC, particularly in remodeling the tumor immune microenvironment. The findings provide a promising strategy for immune combination therapy in TNBC.
期刊介绍：
Amino Acids publishes contributions from all fields of amino acid and protein research: analysis, separation, synthesis, biosynthesis, cross linking amino acids, racemization/enantiomers, modification of amino acids as phosphorylation, methylation, acetylation, glycosylation and nonenzymatic glycosylation, new roles for amino acids in physiology and pathophysiology, biology, amino acid analogues and derivatives, polyamines, radiated amino acids, peptides, stable isotopes and isotopes of amino acids. Applications in medicine, food chemistry, nutrition, gastroenterology, nephrology, neurochemistry, pharmacology, excitatory amino acids are just some of the topics covered. Fields of interest include: Biochemistry, food chemistry, nutrition, neurology, psychiatry, pharmacology, nephrology, gastroenterology, microbiology
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