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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月27日

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  • 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,
  • Xuegang Sun

摘要

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.