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.