Anti-PD-1 synergizes with RFA to suppress abscopal tumors and induce durable memory against recurrence in HCC.

BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is the first-line treatment for early-stage hepatocellular carcinoma (HCC). However, recurrence after curative RFA remains a significant challenge for HCC patients. Although RFA induces an immune response, the anti-tumor effect is often limited by the immunosuppressive tumor microenvironment. Enhancing anti-tumor immunity is essential to improve treatment efficacy and prevent recurrence. In this study, we explore the efficacy and underlying mechanisms of the combination of RFA and anti-PD-1 in suppressing abscopal and recurrent tumors. METHODS: We established a bilateral subcutaneous HCC mouse model and performed complete RFA on the right-flank tumor. Anti-PD-1 or anti-IgG was administered post-RFA. Tumor growth, immune cell profiles, and molecular pathways were assessed using flow cytometry, immunohistochemistry staining, RNA-sequencing, and Western blot. Chemokines released by the tumor were detected by ELISA. An in vivo tumor rechallenge experiment was performed after a complete tumor regression to evaluate the immune memory induced by the RFA+anti-PD-1 treatment. RESULTS: RFA combined with anti-PD-1 significantly suppressed abscopal tumor growth and prolonged survival. Compared with RFA monotherapy, the infiltration of CD8(+)T cells and dendritic cells was significantly increased in the combined treatment group, while PMN-MDSCs were markedly reduced. Mechanistically, the chemokine signaling pathway and JAK-STAT signaling pathway were activated in the tumor of the RFA+anti-PD-1 group with upregulation of CXCL10 to recruit CD8(+)T cells. In addition, the combination therapy induced durable immune memory that inhibited rechallenge tumor outgrowth. CONCLUSIONS: Our study discovered that RFA combined with anti-PD-1 induced anti-tumor immunity to inhibit abscopal tumors and durable immune memory to prevent recurrence, suggesting RFA+anti-PD-1 as a potential therapeutic strategy for multifocal HCC and preventing recurrence.