Targeting hepatocytic TβRI ameliorates liver metastatic outcomes by revitalizing stem-like CD8+ Tex subsets

Hao Wang, Yan Zhou, Yuanyu Tu, Junxiong You, Baogui Gao, Kun Yuan, Shihong Zhong, Changjie Huang, Qinrui Han, Yu Dai, Ye Ma, Qingyuan Zhang, Xinyi Yan, Junjiang Wang (), Xiaorui Wang (), Liang Zhao () and Xuegang Sun ()
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Hao Wang: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Yan Zhou: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Yuanyu Tu: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Junxiong You: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Baogui Gao: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Kun Yuan: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering
Shihong Zhong: Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital
Changjie Huang: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Qinrui Han: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Yu Dai: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Ye Ma: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Qingyuan Zhang: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Xinyi Yan: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine
Junjiang Wang: Guangdong Academy of Medical Sciences, Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital
Xiaorui Wang: Southern Medical University, Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering
Liang Zhao: Southern Medical University, Department of Pathology, Nanfang Hospital
Xuegang Sun: Southern Medical University, The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65615-0

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