Etiology Dependent Differences in Immunotherapy Response and Prognosis Between MASH-HCC and HBV-HCC

The incidence of metabolic dysfunction-associated steatohepatitis related hepatocellular carcinoma is increasing. However, its response to immunotherapy remains unclear. This study aimed to compare the prognosis of patients with MASH-HCC and hepatitis B virus-related HCC (HBV-HCC) under different treatment strategies.

This single-center retrospective study included 218 patients with HCC from 2022 to 2025. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was 1-year overall survival (OS). Kaplan-Meier analysis, Cox regression models, and restricted cubic spline (RCS) analysis were used to evaluate the association between immune cells and prognosis. Stratified and subgroup analyses were also performed.

A total of 136 HBV-HCC and 82 MASH-HCC patients were enrolled in this study. PFS was significantly longer in HBV-HCC patients than in MASH-HCC patients (70.59% vs 41.46%, P<0.001, HR=3.426, 95% CI: 1.668-7.038), while no significant difference in OS was observed (P=0.302). Cox regression indicated that multiple therapeutic modalities were associated with PFS in both subgroups. After stratification by treatment, PFS differences remained prominent in selected interventions. RCS analysis revealed a significant association between CD4⁺ T cell count and PFS (P overall=0.036). Stratification by CD4⁺ T-cell cutoff (354 cells/μL) showed that the prognostic gap between etiologies was diminished in patients with higher CD4⁺ T cell levels, while lower CD4⁺ T cell counts were associated with poorer PFS in MASH-HCC.

MASH-HCC patients showed a trend toward poorer response to ICI therapy compared with HBV-HCC patients, particularly in those with CD4⁺ T cell counts <354 cells/μL. These results suggest that both disease etiology and immune status may contribute to variability in immunotherapy outcomes and warrant consideration in treatment decision making.