Hepatocyte IRE1α–XBP1s axis prevents pro-metastatic niche formation through metabolic rewiring of inflammatory monocytes
Abstract Inositol-requiring enzyme 1α (IRE1α) and the downstream spliced form of X-Box Binding Protein 1 (XBP1s) have been identified as tumor promotors. However, how IRE1α–XBP1s signaling affects tumor progression in a non-cell autonomous manner remains unclear. Here we show that the hepatocyte IRE1α–XBP1s axis unexpectedly inhibits liver metastasis by confining local metainflammation. Genetic ablation of IRE1α or XBP1 in mouse hepatocytes exacerbates liver metastasis due to the accumulation of inflammatory monocytes (IMs). Mechanistically, a non-canonical Forkhead box O1 (FoxO1)-glutamine synthetase (GS) pathway endows the IRE1α- or XBP1-null hepatocytes with the metabolic activity to secrete glutamine, which is necessary and sufficient for IM fitness. Reintroduction of hepatocyte XBP1s or blockade of glutamine metabolism effectively reduces IMs and mitigates disease progression. Importantly, clinical patient survival with liver metastases positively correlates with hepatocyte XBP1s expression. Our study defines a paradigm of hepatocyte–IM interaction that can be leveraged to treat liver metastasis.
Authors
- Nils Halberg (ORCID: https://orcid.org/0000-0002-2943-3147)
- Wei Yang (ORCID: https://orcid.org/0000-0001-8162-033X)
- Grant A. Ramm (ORCID: https://orcid.org/0000-0001-7058-6201)
- Xiaofan Ding (ORCID: https://orcid.org/0000-0003-2565-7757)
- Chonghao Chen (ORCID: https://orcid.org/0000-0003-3919-8598)
- Josh Haipeng Lei (ORCID: https://orcid.org/0000-0002-2058-8054)
- 李小林
- Xiangpeng Chu (ORCID: https://orcid.org/0000-0001-7164-9067)
- Jiajie Hou (ORCID: https://orcid.org/0000-0002-9011-6837)
- Zhi-Bin Zhao (ORCID: https://orcid.org/0000-0003-0691-2556)
- Zeren Yin
- Zhe‐Xiong Lian (ORCID: https://orcid.org/0000-0002-9525-1421)
- Haiyan Zhang (ORCID: https://orcid.org/0009-0002-6401-7090)
- Shiliang Liu (ORCID: https://orcid.org/0000-0001-5830-5171)
- Xin Pei (ORCID: https://orcid.org/0000-0001-9961-6152)
- Minshan Chen
- Hong Pan
- Xiaocong Chen
- Hai Hu
- Peibin Liang
Institutions
- The University of Queensland (AU)
- University of Macau (MO)
- QIMR Berghofer Medical Research Institute (AU)
- Zhejiang Cancer Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Sun Yat-sen University Cancer Center (CN)
- Guangdong Provincial People's Hospital (CN)
- State Key Laboratory of Oncology in South China (CN)
- Hangzhou Institute of Medicine, Chinese Academy of Sciences (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-11-03
- DOI
- https://doi.org/10.1038/s41467-026-78812-2
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00