Interleukin‐37 Enhances Liver NK Cell Cytotoxicity and Improves Recurrence‐Free Survival in Hepatocellular Carcinoma Patients

INTRODUCTION: Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, and postoperative recurrence continues to limit long-term survival. Liver-resident natural killer (NK) cells are key effectors of antitumor immunity in the hepatic microenvironment. Interleukin-37 (IL-37), an anti-inflammatory cytokine, has recently been shown to modulate immune responses and enhance NK-cell activity. METHODS: Liver mononuclear cells were isolated from 24 deceased donors. For functional experiments, liver NK cells from six donors were cultured with interleukin-2 (IL-2) in the presence or absence of IL-37. Flow cytometry was used to evaluate activation markers, and cytotoxicity assays assessed NK cell-mediated tumor lysis. Serum IL-33 and IL-37 levels were measured in 120 patients undergoing liver resection for HCC, and their associations with oncological outcomes were analyzed. RESULTS: IL-37 significantly enhanced NK-cell cytotoxicity, increasing TRAIL and NKp44 expression. Clinically, patients with higher serum IL-37 levels showed improved 5-year recurrence-free survival (35.5% vs. 20.1%, p = 0.02) and a lower incidence of early recurrence. CONCLUSION: IL-37 enhanced liver NK-cell cytotoxicity in experimental analyses, and higher preoperative serum IL-37 levels were associated with improved recurrence-free survival after liver resection for HCC.