Longitudinal Monitoring of GRIm and HCC-GRIm Scores Reveals Immunologically Relevant Prognostic Indicators in Hepatocellular Carcinoma Undergoing TACE Plus ICIs and Anti-VEGF Antibodies/TKIs

Purpose: To investigate the clinical significance and peripheral immunological basis underlying the dynamic changes of the Gustave Roussy Immune (GRIm) score and the hepatocellular carcinoma-specific GRIm (HCC-GRIm) score in unresectable hepatocellular carcinoma (uHCC) patients treated with transarterial chemoembolization (TACE) plus immune checkpoint inhibitors (ICIs) and anti-VEGF antibodies or tyrosine kinase inhibitors (TKIs).

Materials and Methods: This single-center retrospective study included uHCC patients treated with TACE plus ICIs and anti-VEGF antibodies/TKIs from July 2019 to August 2024. Primary outcomes were ORR and DCR after four cycles per mRECIST; secondary outcomes were OS and PFS. GRIm and HCC-GRIm scores were analyzed at baseline, Cycle 2, Cycle 4, and progression in relation to OS. Peripheral immune markers were measured longitudinally and compared between GRIm score groups and response subgroups. PCA was used to integrate GRIm components into an immune-metabolic index (PC1), correlated with immune markers.

Results: Sixty-eight uHCC patients received TACE plus ICIs and anti-VEGF/TKIs. At first evaluation, ORR was 52.9% and DCR 86.8%. After a median follow-up of 18.4 months, median OS was 30.1 months and median PFS 10.6 months. GRIm and HCC-GRIm scores were prognostic only at baseline (GRIm P = 0.011; HCC-GRIm P = 0.001), and patients with persistently low scores had longer OS than those with increasing trajectories. Immunoglobulins (Igλ, Igκ, IgG, IgA) increased overall after treatment, with significant rises in responders but not in non-responders. At baseline, high GRIm scores were associated with elevated Igλ, Igκ, and IgG. In low-score patients, Igλ, Igκ, and IgG increased significantly during treatment. PCA-derived PC1 correlated positively with Igλ, Igκ, IgG, and complement factor B, supporting links between GRIm status, immunoglobulin dynamics, and clinical outcomes.

Conclusion: GRIm and HCC-GRIm scores are effective prognostic indicators only at baseline in uHCC treated with TACE plus ICIs and anti-VEGF/TKIs. Low-score patients demonstrated treatment-related increases in Igλ, Igκ, and IgG, linking GRIm-defined risk, immune activation, and clinical outcomes. Incorporating GRIm dynamics and immunoglobulin monitoring into clinical workflows may improve risk stratification and guide personalized therapy in uHCC.