Supplementary Material for: Gd-EOB-DTPA-Enhanced MRI for Predicting Immunotherapy Response in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis

Introduction: Hepatocellular carcinoma (HCC) harboring CTNNB1 mutations that activate the Wnt/β-catenin pathway demonstrates increased Gd-EOB-DTPA uptake due to overexpressed OATP1B3 (Organic anion transporting polypeptide 1B3) and exhibits immune checkpoint inhibitor (ICI) resistance attributed to an immune-excluded tumor microenvironment (TME) and tumor immune barriers (TIB). This systematic review investigated Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) for predicting immunotherapy response in HCC. Methods: A systematic search of PubMed, Web of Science, and Cochrane was conducted up to September 10, 2025. Studies linking RER > 0.9 on Gd-EOB-DTPA-enhanced MRI to PFS (RECIST 1.1) in immunotherapy-treated patients were included. Following PRISMA 2020/SWiM guidelines, risk of bias was assessed via QUADAS-2. Meta-analysis was performed using JASP (v0.95.4) via a random-effects model with Restricted Maximum Likelihood (REML) estimation. Heterogeneity was assessed using I² and τ². Notably, the Knapp-Hartung adjustment was applied to calculate 95% confidence interval (CI) to ensure robust inference despite the limited study number. Sources of heterogeneity and robustness were explored using subgroup analyses, meta-regression, and sensitivity analyses. Results: Five studies (n = 253; published 2021–2025) were analyzed. RER ≥ 0.9 was identified as a significant predictor of poor response across diverse ICI regimens, with a pooled HR of 5.79 (95% CI: 1.56–21.50; p = 0.020) and individual estimates ranging from 1.58 to 22.04. However, further analysis indicated that anti-VEGF therapy might mitigate this resistance and partially restore ICI efficacy; the association between high RER and poor survival was not statistically significant in the anti-VEGF cohort (HR = 3.39; 95% CI: 0.39–29.14; p = 0.135). Conclusions: To the best of our knowledge, this is the first systematic review evaluating the predictive utility of Gd-EOB-DTPA-enhanced MRI for HCC immunotherapy. Our findings suggest that an RER ≥ 0.9 serves as a potential non-invasive marker for poor treatment response. Notably, the observation that anti-VEGF combination therapy might mitigate this imaging-defined resistance is hypothesis-generating, underscoring the need for prospective studies to validate optimal strategies for patients with high-RER tumors.