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.

objectiveTo investigate the clinical significance and peripheral immunological basis underlying the dynamic changes of 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) combined with immune checkpoint inhibitors (ICIs) and antivascular endothelial growth factor (anti-VEGF) antibodies or tyrosine kinase inhibitors (TKIs).

methodsThis single-center retrospective study included uHCC patients treated with TACE combined with ICIs and anti-VEGF antibodies or TKIs between July 2019 and August 2024. Primary outcomes were the objective response rate (ORR) and disease control rate (DCR), assessed at the first treatment evaluation at the end of the fourth cycle based on mRECIST criteria; secondary outcomes included overall survival (OS) and progression-free survival (PFS). GRIm and HCC-GRIm scores were calculated at four key timepoints: baseline (Cycle 0), second cycle (Cycle 2), fourth cycle (Cycle 4), and disease progression (PD). Their distributions and trajectory patterns were analyzed in relation to OS. Peripheral immune markers were measured at each timepoint to characterize immune response dynamics. Comparisons of immune marker levels and trends were performed between GRIm high and low score groups, as well as between objective responders (OR) and nonresponders (nOR) across treatment stages. Principal component analysis (PCA) was applied to derive an integrated immune-metabolic index (PC1) from GRIm components, and its correlations with immune markers were evaluated.

resultsA total of 68 uHCC patients treated with TACE plus ICIs and anti-VEGF antibodies/TKIs were included. At the first evaluation, the ORR was 52.9% and the DCR 86.8%. After a median follow-up of 18.4 months, the cohort showed a median overall survival (mOS) of 30.1 months and a median progression-free survival (mPFS) of 10.6 months. GRIm and HCC-GRIm scores remained stable across treatment phases, with their prognostic value for OS confined to baseline (Cycle 0) assessment (GRIm: p = 0.011; HCC-GRIm: p = 0.001). Patients with persistently low scores had significantly longer OS than those with increasing trajectories (GRIm: p = 0.025; HCC-GRIm: p = 0.048). Following treatment initiation, Igλ (p = 0.001), Igκ (p = 0.001), IgG (p = 0.002), and IgA (p = 0.001) levels showed an overall upward trend. At the first evaluation, these markers were significantly elevated in OR compared to baseline (Igλ [p = 0.022], Igκ [p = 0.032], IgG [p = 0.036], IgA [p = 0.019]), whereas no significant changes were observed in nOR (all p > 0.05). Among all timepoints, significant differences between high and low GRIm score groups were noted only at baseline, with higher Igλ (p = 0.001), Igκ (p = 0.014), and IgG (p = 0.009) levels in the high-score group. In patients with low GRIm scores, linear regression revealed increasing trends in Igλ (p = 0.042), Igκ (p = 0.017), and IgG (p = 0.019) during treatment. PCA showed PC1 correlated positively with Igλ (r = 0.259, p = 0.033), Igκ (r = 0.293, p = 0.015), IgG (r = 0.355, p = 0.003), and complement factor B (CFB; r = 0.314, p = 0.009).

conclusionThe GRIm and HCC-GRIm scores were shown to be effective prognostic indicators only at baseline in uHCC patients treated with TACE combined with ICIs and anti-VEGF antibodies or TKIs. Patients with low GRIm scores demonstrated treatment-associated increases in Igλ, Igκ, and IgG levels. Igλ, Igκ, and IgG represent measurable links between GRIm-defined risk categories, immune activation following treatment, and clinical outcomes. Integration of GRIm dynamics and immunoglobulin monitoring into clinical workflows may enhance risk stratification and support personalized treatment strategies in advanced HCC.