Dynamics of peripheral immune signature identified by multi-omics and its impact on recurrence after radiofrequency ablation of hepatocellular carcinoma.

Background: Radiofrequency ablation (RFA) has emerged as a commonly used approach for early-stage hepatocellular carcinoma (HCC) patients. Exploring immunity changes after RFA therapy is helpful for reducing recurrence. Methods: In this study, we enrolled 12 patients with HCC with their 47 blood samples, including before and after complete RFA therapy. We performed an integrative analysis of the transcriptome and methylome, investigated using a novel self-developed methylation array (HYGEIA panel). Core analyses included differential analyses of both transcriptome and methylome, DIABLO-based multi-omics integration, gene set enrichment analysis, and time-series gene clustering with visualization. Results: Our study elucidated the complex effect of the location of CpG site methylation on their corresponding gene transcription; 58.44% of CpG sites were located in the promoter (≤1 kb) region and mainly negatively correlated with gene expression. RFA treatment in HCC patients activated antigen processing and presentation and Th1 and Th2 cell differentiation signaling pathways. The anti-tumor immune responses induced by RFA therapy persisted for less than 9 months in recurrent patients. Meanwhile, the ability of T-cell differentiation in HCC patients was a potential factor to prevent recurrence. Conclusion: These findings elucidated the dynamic peripheral immune remodeling post-RFA and identified host T-cell fitness as a key determinant of recurrence, providing a rationale for combining RFA with immunotherapy to prolong protective immune responses.