COX-2/PGE2 axis blockade with celecoxib enhances anti-PD-1 efficacy by activating natural killer cells for residual hepatocellular carcinoma after radiofrequency ablation

Background and aims Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but incomplete ablation and recurrence of residual tumors remain significant challenges, partly due to local inflammation and elevated COX-2 levels in the tumor microenvironment. This study aims to investigate the potential of combining celecoxib, a COX-2 inhibitor, with anti-PD-1 monoclonal antibody (αPD-1) to enhance anti-tumor efficacy and activate immune responses. Methods In vitro, ELISA was used to assess the effects of radiofrequency heat treatment and celecoxib on PGE 2 secretion by Hepa1-6 cells. Scanning electron microscopy, flow cytometry, and CCK-8 assays were employed to evaluate the function and cytotoxic activity of NK92 cells against Hepa1-6 cells. In vivo, orthotopic HCC mice were divided into five groups to evaluate tumor volume, pathology, and survival. The role of celecoxib in the COX-2/PGE 2 /NK cell axis and its impact on NK cell immune function were investigated. Results In vitro experiments showed that celecoxib reversed PGE 2 -mediated suppression of NK cell function and cytotoxic activity against HCC cells by inhibiting PGE 2 secretion. In vivo, orthotopic HCC mice treated with celecoxib and αPD-1 exhibited significantly reduced tumor volumes, attenuated the infiltration and activation of NK cells, and prolonged survival compared to control groups. The combination therapy also demonstrated a notable abscopal-like effect, inhibiting metastatic tumor growth and activating systemic immunity. Conclusions Taken together, these findings suggest that celecoxib combined with αPD-1 represents a promising strategy for treating residual HCC after RFA, with enhanced anti-tumor effects and good safety. Graphical abstract