ArticleJournal of translational medicine2025
Inhibition of VEGF signaling prevents exhaustion and enhances anti-leukemia efficacy of CAR-T cells via Wnt/β-catenin pathway.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Mechanobiology of CAR-T cell therapy: regulatory mechanisms and strategies for enhanced antitumor immunity.Journal of translational medicine · 2026Review
- Review
- Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy.Journal of translational medicine · 2026Review
- CAR-engineered cell therapies: current understandings and future perspectives.Molecular biomedicine · 2026Review
- Wnt signaling as a regulator of memory T cells: implications for CAR-T cell therapy.Frontiers in immunology · 2026Review
- Post-Translational Modifications in Cancer-Associated CD8⁺ T-Cell Exhaustion: Mechanisms and Therapeutic Opportunities.International journal of biological sciences · 2026Review
- Overcoming Resistance and Relapse in CAR-T and CAR-NK Cell Therapies: From Bench to Bedside.Research (Washington, D.C.) · 2026Article
- Research progress on resistance mechanisms to CAR-T cell therapy in diffuse large B-cell lymphoma.Frontiers in oncology · 2026Review
- Next-generation CAR-T cells design: leveraging tumor features for enhanced efficacy.Molecular cancer · 2025Review
- Immunotherapy in central nervous system tumors.International journal of surgery (London, England) · 2025Review
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Authors and funding
12 authors.
Funding
Abstract
backgroundCurrent challenges in Chimeric Antigen Receptor (CAR) -T cell therapy for hematological cancers include T cell exhaustion and limited persistence, which contribute to cancer relapse.
methodsThe effects of Axitinib, a VEGFR inhibitor, on the biological functions of CAR-T cells in vitro and in vivo were investigated by comparing CAR-T cells pre-treated ex vivo with Axitinib, as well as utilizing a B-ALL mouse model. Real-time quantitative PCR and Western blotting were employed to detect the expression of molecules related to differentiation, exhaustion, and the Wnt pathway in CAR-T cells. Flow cytometry was used to assess changes in CAR-T cell differentiation, exhaustion, activation, apoptosis, proliferation, and cytokine secretion. Western blotting and flow cytometry were used to assess changes in VEGFR expression. Bioluminescence imaging, flow cytometry, and immunohistochemistry (IHC) analysis were used to evaluate changes in tumor burden in mice receiving different treatments, while hematoxylin and eosin (H&E) staining were used to monitor histological changes in the liver and spleen of mice.
resultsAxitinib treatment notably reduced CAR-T cell exhaustion and terminal differentiation both under tonic signaling and tumor antigen exposure scenarios. Furthermore, CAR-T cells pretreated with Axitinib demonstrated enhanced anti-tumor efficacy and prolonged survival in vivo. Mechanistically, Axitinib treatment upregulated the Wnt/β-catenin signaling pathway in CAR-T cells. Using agonists/inhibitors of the Wnt/β-catenin pathway could respectively mimic or counteract the effects of Axitinib on CAR-T cell exhaustion and differentiation. CAR-T cells treated with Axitinib can inhibit the VEGFR2 pathway. CAR-T cells treated with anti-VEGFR2 antibody can activate the Wnt/β-catenin pathway and prevent CAR-T cell exhaustion.
conclusionAxitinib confers resistance to exhaustion in CAR-T cells by modulating the Wnt/β-catenin signaling pathway.
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