Tumor metastasis co-opts liver hematopoiesis to promote immunosuppression
Cancer-associated hematopoietic abnormalities contribute to systemic immunosuppression. However, whether tumors can initiate localized extramedullary hematopoiesis to suppress antitumor immunity remains unclear. In this study, we identify a distinct form of hepatic hematopoiesis driven by liver metastasis–associated hematopoietic stem cells (LM-HSCs). Liver metastases establish ectopic periportal hematopoietic niches that recruit bone marrow HSCs through Kupffer cell–dependent C-C motif chemokine receptor 1 (CCR1) signaling. Although LM-HSCs retain self-renewal and multipotency, cAMP response element–binding protein (CREB) activation skews their differentiation toward the myeloid lineage, particularly annexin A1–positive (ANXA1 + ) immature neutrophils. These neutrophils produce glucocorticoids, which activate glucocorticoid receptor signaling in a paracrine manner and induce immune checkpoint receptor expression and functional anergy in CD8 + T and natural killer cells. Collectively, these findings suggest that liver metastases reprograms hepatic hematopoiesis to promote immunosuppression.
Authors
- Naiheng Lin
- Le Zhang (ORCID: https://orcid.org/0000-0003-4683-5209)
- Ying Han (ORCID: https://orcid.org/0000-0003-4481-0534)
- Aoyuan Cui (ORCID: https://orcid.org/0000-0003-2037-9241)
- Xuege Wang (ORCID: https://orcid.org/0000-0001-7913-7234)
- Beitao Xu
- Jun Qin (ORCID: https://orcid.org/0000-0002-2263-128X)
- Wei Lü (ORCID: https://orcid.org/0000-0002-2391-5444)
- Junjie Peng (ORCID: https://orcid.org/0000-0002-0371-4960)
- Zhengquan Yu (ORCID: https://orcid.org/0000-0001-8696-2013)
- Yannan Lian
- Yu Li (ORCID: https://orcid.org/0000-0001-8815-6816)
- Lan Wang (ORCID: https://orcid.org/0000-0003-3545-5059)
- Xiaoming Wang (ORCID: https://orcid.org/0000-0003-0679-9768)
- Guihua Wang (ORCID: https://orcid.org/0000-0001-5423-9357)
- Yaqi Li (ORCID: https://orcid.org/0000-0001-5555-4711)
- Xin Zeng (ORCID: https://orcid.org/0000-0002-7562-9909)
- Zige Jin
- Jiacheng Guo (ORCID: https://orcid.org/0009-0005-7555-1995)
- Yongqiang Gu
- Qiang Pan
- Guoying Zhang
- Ni Li
- Wei Zhang (ORCID: https://orcid.org/0009-0004-7839-0771)
Institutions
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Zhengzhou University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Tongji Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Jinfeng Laboratory (CN)
- Huazhong University of Science and Technology (CN)
- China Agricultural University (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Science
- Published
- 2026-11-05
- DOI
- https://doi.org/10.1126/science.aea3046
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00