Liver ischemia-reperfusion promotes tumor metastasis via neutrophil-endothelial interactions: targeting ICAM1 to prevent metastatic recurrence

Liver ischemia-reperfusion (IR) injury, commonly encountered in liver surgery and transplantation, has been linked to enhanced metastatic potential in hepatic tumors. The mechanisms underlying this process, however, remain poorly understood. In this study, we utilized mouse models of hepatocellular carcinoma (HCC) and colorectal cancer (CRC) to investigate the role of liver IR in tumor metastasis. We employed ICAM1 blockade with atorvastatin to assess its impact on tumor progression. The effects of neutrophil depletion and ICAM1 inhibition on tumor metastasis were evaluated through in vivo and in vitro assays, while clinical data from HCC patients were analyzed for correlations with ICAM1 expression and prognosis. Our results demonstrate that liver IR significantly increases liver and lung metastasis, decreases survival, and facilitates tumor cell infiltration through neutrophil-mediated interactions. ICAM1 expression was upregulated in liver endothelial cells following IR, promoting neutrophil adhesion and tumor cell transmigration. Atorvastatin treatment reduced ICAM1 expression, attenuated neutrophil recruitment, and inhibited tumor metastasis in both liver and lung. Clinical analysis showed that high ICAM1 expression in HCC tissues was associated with poor prognosis, increased neutrophil infiltration, and worse overall survival (OS) and recurrence-free survival (RFS). This study uncovers the critical role of the ICAM1-neutrophil axis in mediating liver IR-induced metastasis. Targeting ICAM1, particularly with atorvastatin, presents a promising therapeutic strategy to prevent metastatic recurrence in liver surgery patients and improve clinical outcomes in HCC. This study is a retrospective observational analysis of clinical data from HCC patients, with no prospective assignment of interventions by the investigators. As per ICMJE guidelines, clinical trial registration is not required for purely observational studies where intervention assignment is not at the discretion of the investigator.