Targeting hepatocytic TβRI ameliorates liver metastatic outcomes by revitalizing stem-like CD8+ Tex subsets
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Le résumé fourni par la source
Stem-like CD8⁺ exhausted T cells (Tex) sustain antitumor immunity, whereas TGFβ signaling acts as a major immunosuppressive pathway. In patients with colorectal liver metastases, we observe that elevated TβRI expression in peri-metastatic hepatocytes correlates with poor prognosis. We therefore investigate whether disrupting hepatocytic TGFβ signaling can reinvigorate stem-like CD8⁺ Tex cells to restrict liver metastasis. In support of this hypothesis, mice with hepatocyte-specific TβRI depletion exhibit reduced liver metastatic burden across multiple tumor models. Mechanistically, hepatocytic TβRI blockade suppresses Galectin-9 secretion, which reshapes the transcriptional program of intra-tumoral CD8⁺ T cells. This reprogramming promotes a phenotypic transition from terminal exhaustion toward stem-like and effector states, yielding T cell subsets with enhanced metastasis-control capacity. Importantly, this axis functions independently of macrophages and CD4⁺ T cells. Furthermore, therapeutic delivery of Galunisertib using choline-modified lipid nanoparticles synergizes with αPD-1, fostering the conversion of exhausted CD8⁺ T cells into responsive Ly108⁺CX3CR1⁺ subsets and suppressing liver metastases. Collectively, our results identify hepatocyte TGFβ signaling as a targetable checkpoint against liver metastases. How TGF-β regulates liver metastasis remains further investigation. The authors here find that TβRI blockade in hepatocytes decreases liver metastatic progression via revitalizing stem-like CD8⁺ Tex subsets, and an LNP encapsulated with the TβRI inhibitor Galunisertib synergizes with αPD-1 to ameliorate liver metastasis
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Targeting hepatocytic TβRI ameliorates liver metastatic outcomes by revitalizing stem-like CD8+ Tex subsets
- Date Crossref
- 27/11/2025
- Éditeur
- Springer Science and Business Media LLC
- 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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State Administration of Traditional Chinese Medicine of the People's Republic of China pays non établi dans la noticeOrganisme public
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TCM-Intigrated Cancer Center of Southern Medical University State Key Laboratory of Organ Failure Research pays non établi dans la noticeÉtablissement de santé
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Southern Medical University Department of Hepatology pays non établi dans la noticeUniversité ou école supérieure
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Nanfang Hospital pays non établi dans la noticeÉtablissement de santé
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Guangdong Academy of Medical Sciences pays non établi dans la noticeÉtablissement de santé
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Guangdong Provincial People's Hospital Department of Gastrointestinal Surgery pays non établi dans la noticeÉtablissement de santé
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School of Traditional Chinese Medicine The Key Laboratory of Molecular Biology pays non établi dans la noticeUniversité ou école supérieure
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School of Biomedical Engineering Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering pays non établi dans la noticeUniversité ou école supérieure
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School of Basic Medical Sciences Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology pays non établi dans la noticeUniversité ou école supérieure
State Administration of Traditional Chinese Medicine of the People's Republic of China, State Key Laboratory of Organ Failure Research — TCM-Intigrated Cancer Center of Southern Medical University et Department of Hepatology — Southern Medical University, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.