Clathrin mediated endocytosis targeting chimera for targeted membrane proteins degradation and enhance CAR-T cell anti-tumor therapy
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Le résumé fourni par la source
Rationale: T cell exhaustion, mediated by the expression of inhibitory receptor proteins, significantly reduces their anti-tumor efficacy.Therefore, strategies aimed at degrading membrane proteins have emerged as promising approaches for enhancing the therapeutic effectiveness of Chimeric Antigen Receptor (CAR) T cells and improving cancer treatment outcomes.Methods: In this study, we developed a Clathrin-Mediated Endocytosis Targeting Chimera (CleTAC), an innovative platform designed to facilitate membrane protein degradation via the clathrin-mediated endocytosis pathway.CleTAC employs the YVKM motif to interact with the AP2 complex, driving the internalization of targeted membrane proteins (proteins of interest, POI) along with associated cell membrane components.These internalized complexes are subsequently trafficked to lysosomes for degradation.We conducted multiple validations using flow cytometry, Western blotting, and in vitro and in vivo experiments to verify its degradation efficiency.Additionally, we integrated CleTAC targeting CTLA4 membrane proteins into a CAR construct and evaluated its impact on CAR-T cell functionality and tumor suppressive efficacy using both cellular assays and animal tumor models.Results: We demonstrated that CleTAC effectively and specifically mediates the degradation of EGFP and CTLA4 proteins on the cell surface.When incorporated into a CAR construct, CleTAC targeting CTLA4 enhanced CAR-T cell anti-tumor activity, as evidenced by improved functional assays and tumor suppression in animal models.These findings establish CleTAC as a versatile and effective tool for modulating membrane protein levels and enhance anti-tumor efficacy in CAR-T cells.Conclusions: Our results highlight CleTAC as a promising therapeutic tool with substantial clinical potential to significantly enhance CAR-T cell therapy and advance current oncology treatment strategies.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Clathrin mediated endocytosis targeting chimera for targeted membrane proteins degradation and enhance CAR-T cell anti-tumor therapy
- Date Crossref
- 01/01/2026
- Éditeur
- Ivyspring International Publisher
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Nanchang University Institute of Neuroscience pays non établi dans la noticeUniversité ou école supérieure
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First Affiliated Hospital of Jiangxi Medical College Department of Neurosurgery pays non établi dans la noticeÉtablissement de santé
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Second Affiliated Hospital of Nanchang University pays non établi dans la noticeÉtablissement de santé
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Third Affiliated Hospital of Nanchang University pays non établi dans la noticeÉtablissement de santé
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First Affiliated Hospital of Nanchang University pays non établi dans la noticeÉtablissement de santé
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JXHC key Laboratory of Neurological medicine pays non établi dans la noticeStructure de recherche
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Jiangxi Province Key Laboratory of Neurological Diseases pays non établi dans la noticeStructure de recherche
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School of Pharmacy pays non établi dans la noticeUniversité ou école supérieure
Institute of Neuroscience — Nanchang University, Department of Neurosurgery — First Affiliated Hospital of Jiangxi Medical College et Second Affiliated Hospital of Nanchang University, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.