Targeting the aHSC-PGE2-NK cell axis overcomes immunosuppression and inhibits liver metastasis in fibrotic liver

Jiao-Jiao Tang; Can Chen; Zi-Yue Guan; Zhen-Hua Zhu; Yu-Fei Pan; Ze-Yuan Fu; Jing-Wen Zhu; Dan Cao; Hong-Yang Wang; Le-Xing Yu

doi:10.1016/j.canlet.2026.218450

Targeting the aHSC-PGE₂-NK cell axis overcomes immunosuppression and inhibits liver metastasis in fibrotic liver

Cancer Lett. 2026 Mar 31:652:218450. doi: 10.1016/j.canlet.2026.218450. Online ahead of print.

Authors

Jiao-Jiao Tang¹, Can Chen², Zi-Yue Guan³, Zhen-Hua Zhu⁴, Yu-Fei Pan³, Ze-Yuan Fu³, Jing-Wen Zhu⁵, Dan Cao³, Hong-Yang Wang⁶, Le-Xing Yu⁷

Affiliations

¹ Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, 200438, China.
² Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350000, China.
³ National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China.
⁴ Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China.
⁵ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
⁶ Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, 200438, China; National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China. Electronic address: hywangk@vip.sina.com.
⁷ National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China; International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China. Electronic address: yulx001@163.com.

PMID: 41933572
DOI: 10.1016/j.canlet.2026.218450

Abstract

Liver metastasis (LM) is a major cause of cancer-related mortality, driven largely by dynamic interactions between disseminated tumor cells (DTCs) and the liver microenvironment (LME). Liver fibrosis, a pathological condition characterized by the disruption of the LME and imposing a significant global health burden, is primarily orchestrated by activated hepatic stellate cells (aHSCs). However, the precise mechanisms through which liver fibrosis facilitates LM are poorly understood. Here, we demonstrated that liver fibrosis potently enhanced LM by promoting the early hepatic colonization of tumor cells in an aHSC-dependent manner. Mechanistically, we identified prostaglandin E₂ (PGE₂), secreted by aHSCs, as a key mediator that disrupted natural killer (NK) cell immune surveillance. Either the depletion of aHSCs or pharmacological inhibition of the PGE₂-synthesizing enzyme Cyclooxygenase-2 (COX-2) with Celecoxib (CLX) restored NK cell function and suppressed LM. Notably, CLX treatment synergized with anti-NKG2A-based immunotherapy, significantly boosting its efficacy against LM in the fibrotic liver. Our findings unveil a critical "aHSC-PGE₂-NK cell" axis in liver fibrosis-induced immunosuppression and provide a compelling therapeutic strategy for the clinical management of LM.

Keywords: Celecoxib; Hepatic stellate cells; Liver fibrosis; Liver metastasis; NK cells; PGE(2); Tumor microenvironment.