Work

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

Year: 2025

Type: article

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. 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

Source: Nature Communications

DOI: 10.1038/s41467-025-65615-0