Pre-Treatment HBV Activation Modulates Circulating Immune Markers in Hepatocellular Carcinoma Patients Undergoing TACE Plus ICIs and Anti-VEGF Antibodies/TKIs

Lihao Qin,1,* Linzhou Zhu,2,* Yu Wang,1,* Hao Yang,1 Jian Shen,1 Xiaoli Zhu1 1Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China; 2Department of Epidemiology and Biostatistics, School of Public Health, Medical College of Soochow University, Suzhou, 215021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoli Zhu, Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China, Email [email protected]: To evaluate the impact of pre-treatment hepatitis B virus (HBV) activation on peripheral immune status and treatment response in unresectable hepatocellular carcinoma (uHCC) patients undergoing transarterial chemoembolization (TACE) combined with immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor (anti-VEGF) antibodies or tyrosine kinase inhibitors (TKIs), and to explore the underlying immunological basis.Methods: This single-center retrospective study included uHCC patients treated with TACE plus ICIs and anti-VEGF antibodies or TKIs between July 2019 and September 2024. Patients were categorized into inactive and active HBV infection groups based on pre-treatment HBV DNA levels. A 1:2 propensity score matching (PSM) was used to minimize confounding. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Peripheral immune markers were assessed at baseline (Cycle0), Cycle2, and Cycle4. Intergroup comparisons and regression analyses were performed to examine associations among HBV activation, immune changes, and objective response (OR).Results: A total of 70 patients were enrolled, and 53 were retained after PSM (26 with inactive and 27 with active HBV infection). Median follow-up was 16.6 months; median OS and PFS were 30.1 and 10.6 months, respectively. At Cycle0, serum IgA levels were higher in the active HBV infection group [3.38 (2.72– 4.60) vs 2.70 (2.21– 3.32) g/L, P = 0.018], and HBV DNA showed a linear association with baseline IgA (P = 0.042). IgA increased significantly from Cycle0 to Cycle2 in the inactive HBV infection and OR groups but not in their counterparts. ΔIgA (Cycle2–Cycle0) was independently associated with OR (OR = 0.446, P = 0.041), while baseline IgA independently predicted ΔIgA (β = – 0.260, P = 0.011). No significant OS or PFS differences were observed between HBV activation groups overall, although a trend toward worse OS appeared in the nOR subgroup (P = 0.058).Conclusion: Pre-treatment HBV activation is linked to altered baseline immune profiles, particularly elevated IgA, and influences early IgA dynamics. Early IgA changes independently predict early treatment response, supporting the integration of IgA-based immune profiling into personalized strategies for HBV-related uHCC.Keywords: hepatocellular carcinoma, hepatitis B virus, TACE, prognosis, immune microenvironment