A monocyte-derived blood transcriptomic signature reveals systemic immunosuppression in HCC and partial reversal following curative therapy.

Background: Liver ablation or resection can cure early-stage hepatocellular carcinoma (HCC), yet late diagnosis and high relapse rates hinder long-term survival. We sought to delineate how tumor burden-and its removal-reshape the systemic immune transcriptome and extract blood-based signatures with diagnostic and prognostic potential. Method: Peripheral blood mononuclear cells (PBMCs) from six early-stage HCC patients were subjected to single-cell RNA sequencing (scRNA-seq) both prior to and 1-3 months following curative therapy, alongside six age-matched healthy controls. The data were integrated with independent bulk PBMC transcriptomes and public single-cell datasets of paired tumor and adjacent liver immune cells. Result: Pre-therapy PBMCs displayed an immunosuppressive transcriptional program characterized by elevated TGF beta signaling and ubiquitin-mediated proteolysis. Curative therapy attenuated these pathways and partially restored interferon responses, cytotoxic gene expression, and intercellular communication, although the values remained below healthy levels. We cross-validated these features in tissue, identifying concordant immunosuppressive signatures in tumor versus adjacent-liver immune cells. An immunosuppressive CD14 Conclusion: Early-stage HCC induces a reversible, systemic immunosuppressive transcriptome captured by a monocyte-derived 23-gene blood signature; tumor removal partially restores this profile within three months. These results highlight the potential of blood-derived monocyte signatures as noninvasive biomarkers of HCC-associated immunosuppression and clinical outcome.