Distinct immune signatures define hepatitis D- versus hepatitis B-associated hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Hepatitis D is the most severe form of viral hepatitis. However, the clinical, virological, and systemic inflammatory characteristics of HDV-associated HCC remain insufficiently characterized.

In this single-center retrospective study, we identified 162 patients with HCC due to chronic hepatitis D (HDV-HCC; n=54) or chronic hepatitis B (HBV-HCC; n=108). Plasma levels of 92 soluble inflammatory mediators (SIMs) were quantified using proximity extension assay in HCC patients [HBV-HCC (n=50), HDV-HCC (n=30), and matched non-HCC controls (HBV=19, HDV=17)].

At the time of HCC diagnosis, patients with CHD were younger, had more impaired liver synthesis and detoxification function, and lower levels of AST, CRP, and leukocytes. HDV-HCCs presented with smaller tumors, less frequent portal vein infiltration, and more often fulfilled Milan criteria (all p<0.01). Systemic immune profiling revealed distinct inflammatory patterns between both etiologies. Compared with HBV-HCC, HDV-HCC was characterized by a comparatively stronger IL-10-associated immunoregulatory signature, whereas HBV-HCC exhibited a more pronounced pro-inflammatory profile involving IL-6- and phosphorylation- and proliferation-associated signaling. Despite these differences, event-free survival did not differ between groups.

HBV-HCC more frequently presented with advanced tumor stage, whereas HDV-HCC was associated with more severe underlying liver disease but smaller tumors. Importantly, HBV-associated and HDV-associated HCC exhibit distinct systemic inflammatory signatures, potentially reflecting differences in systemic immune regulation between etiologies. These findings may have implications for biomarker development and future etiology-specific therapeutic strategies.