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 PGE2 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/PGE2/NK cell axis and its impact on NK cell immune function were investigated. RESULTS: In vitro experiments showed that celecoxib reversed PGE2-mediated suppression of NK cell function and cytotoxic activity against HCC cells by inhibiting PGE2 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.