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

Abstract

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.

Keywords

Radiofrequency ablation (RFA) / Hepatocellular carcinoma (HCC) / Abscopal effect / Anti-programmed cell death protein 1 (αPD-1)

Authors' contributions

Kai Lei: Writing e original draft, Validation, Project admin-istration, Methodology, Investigation, Formal analysis, Data cura-tion, Conceptualization. Shuang Li: Writing e original draft, Validation, Methodology, Investigation, Formal analysis, Data curation. Jiale Chen: Validation, Methodology, Investigation. Zebin Chen: Writing e review & editing, Supervision. Fang Wang: Writing e review & editing, Supervision. Xuezhen Zeng: Writing e review & editing, Supervision, Project administration, Methodol-ogy, Investigation, Funding acquisition, Conceptualization.

Data availability statement

The data contained in this manuscript or supplementary ma-terial will be made available upon request from the corresponding author.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This study is funded by the National Natural Science Foundation of China to Xuezhen Zeng (No. 82372777) and the Kelin Foundation for Distinguished Young Scholars to Xuezhen Zeng (No. R07014).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2025.05.003.

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