Hepatocyte-derived LRG1 primes the liver for metastasis and impairs immunotherapy
The liver undergoes active remodeling by the primary tumor prior to metastatic spread. However, the mechanisms by which hepatocytes dictate the liver-specific tropism of tumors remain elusive. Here, we identify hepatocyte-derived leucine-rich alpha-2-glycoprotein 1 (LRG1) as a key mediator of liver premetastatic niche (PMN) formation. Clinically, elevated serum LRG1 levels are correlated with an increased risk of liver metastasis in patients and multiple mouse models. Mechanistically, LRG1 remodels the hepatic microenvironment by driving immunosuppressive neutrophil accumulation, impairing the function of effector T cells and dendritic cells, and enhancing angiogenesis in the liver, thereby fostering a prometastatic landscape. Hepatocyte-specific ablation of LRG1 dampens premetastatic niche formation and significantly reduces the metastatic burden in vivo. Hepatic LRG1 induced by tumor-associated inflammation via IL-6/STAT3 signaling promotes liver metastasis through the formation of TGFBR/PI3K/AKT axis-driven neutrophil extracellular traps (NETs). Importantly, therapeutic blockade of LRG1 not only suppressed liver metastasis but also reprogrammed the hepatic niche toward an immune-activated state, sensitizing tumors to anti-PD-1 therapy. Collectively, our findings reveal a hepatocyte-LRG1 axis that drives liver premetastatic niche remodeling and highlight LRG1 as a promising target for the prevention and treatment of liver metastasis.
Authors
- Zhitong Niu (ORCID: https://orcid.org/0009-0000-0384-6894)
- Bing Cheng (ORCID: https://orcid.org/0000-0002-5724-5725)
- Yingzhen Weng
- Qi Tang (ORCID: https://orcid.org/0000-0002-4497-0469)
- Guojie Long
- Xiangjun Qian
- jinxin Chen (ORCID: https://orcid.org/0000-0003-2561-7958)
- Zheyu Zheng (ORCID: https://orcid.org/0000-0002-8008-1925)
- Panpan Wang (ORCID: https://orcid.org/0000-0003-4542-2859)
- Ronghua Zhang (ORCID: https://orcid.org/0000-0002-4259-0796)
- Tao Su (ORCID: https://orcid.org/0000-0003-1876-700X)
- Xiaoming Huang (ORCID: https://orcid.org/0000-0003-3710-0171)
- Qiufeng Liu
- Danjie Luo
- J. V. K. Tan (ORCID: https://orcid.org/0009-0005-7437-7972)
- Q. Yu
- W Pan
- Tao Ma
- Chaoyin Wei
- Qian Xiao
- Yue Jiang
- Yufeng Chen
- Wenyu Wang (ORCID: https://orcid.org/0000-0001-8947-4867)
Institutions
- Agency for Science, Technology and Research (SG)
- Sun Yat-sen University (CN)
- Jinan University (CN)
- National University of Singapore (SG)
- Sixth Affiliated Hospital of Sun Yat-sen University (CN)
- Duke-NUS Medical School (SG)
- Tianma Microelectronics (China) (CN)
- National Cancer Centre Singapore (SG)
- Henan Cancer Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- First Affiliated Hospital of Jinan University (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Cellular and Molecular Immunology
- Published
- 2026-04-10
- DOI
- https://doi.org/10.1038/s41423-026-01408-9
- Primary Topic
- Clusterin in disease pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Fundamental Research Funds for the Central Universities
- Basic and Applied Basic Research Foundation of Guangdong Province