Work

Sex disparity of liver cancer recurrence following surgery: sex-determining region Y gene promotes immunosuppressive microenvironment and favors metastasis

Year: 2025

Type: article

Abstract: BACKGROUND: Male sex is a risk factor of the development and prognosis of primary liver cancers. However, sex difference of tumor recurrence following curative resection and the underlying mechanism need to be clarified. METHODS: Sex and outcomes among patients undergoing resection for hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) were investigated in two international multi-institutional databases. Murine model of postoperative HCC recurrence was used following hepatic ischemia-reperfusion (I/R) injury to mimic surgical injury in hepatocyte-specific sex-determining region Y gene (SRY) knock-in (KI) and knockout (KO) mice, as well as wildtypes (WTs). RESULTS: Men had a significantly worse recurrence-free survival (RFS) following curative resection of HCC or ICC versus women (5-year RFS: HCC, men 30.0% vs. women 43.9%, P = 0.041; ICC, men 18.7% vs. women 26.8%, P = 0.006, respectively) in the matched cohort. Male mice consistently developed larger recurrent tumor versus females after hepatic I/R injury, accompanied by increased polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and decreased CD8 + T cells. Of note, SRY KI in both male and female mice increased, whereas SRY KO decreased tumor recurrence upon I/R injury. Moreover, SRY was associated with increased immunosuppressive PMN-MDSCs and decreased CD8 + T cells in both patient and murine livers after I/R injury. Mechanistically, hepatocyte SRY recruited PMN-MDSCs to the liver microenvironment following I/R injury through NF-κB-dependent CXCL1 secretion. CONCLUSIONS: Men are more likely to recur than women after liver resection of liver cancers. SRY promotes immunosuppressive microenvironment in the liver and accounts for male susceptibility of liver cancer recurrence. Targeting SRY-NFκB-CXCL1 axis may have potential value in male-specific surveillance and immunomodulatory therapy of primary liver cancer.

Source: International Journal of Surgery

DOI: 10.1097/js9.0000000000002900