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

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.