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.

引言：携带可激活Wnt/β-连环蛋白通路的CTNNB1基因突变的肝细胞癌（HCC），由于过表达有机阴离子转运多肽1B3（OATP1B3，Organic anion transporting polypeptide 1B3）而表现出Gd-EOB-DTPA摄取增加，且因免疫排斥型肿瘤微环境（TME）与肿瘤免疫屏障（TIB）而呈现免疫检查点抑制剂（ICI）耐药性。本系统综述旨在探讨Gd-EOB-DTPA增强磁共振成像（MRI）在预测HCC免疫治疗应答中的应用价值。
方法：本研究于2025年9月10日前对PubMed、Web of Science及Cochrane数据库进行系统性检索，纳入探讨Gd-EOB-DTPA增强MRI中RER>0.9与接受免疫治疗患者的无进展生存期（PFS，基于实体瘤疗效评价标准1.1版（RECIST 1.1））相关性的研究。依据PRISMA 2020/SWiM指南，采用QUADAS-2量表评估偏倚风险。使用JASP软件（v0.95.4）采用限制性最大似然（REML）估计的随机效应模型进行荟萃分析，通过I²与τ²统计量评估异质性。鉴于纳入研究数量有限，采用Knapp-Hartung校正计算95%置信区间（CI）以保证推断的稳健性。通过亚组分析、荟萃回归及敏感性分析探讨异质性来源与结果稳健性。
结果：共纳入5项研究（n=253；发表于2021-2025年）并进行分析。RER≥0.9可作为多种ICI治疗方案下疗效不佳的显著预测因子，合并风险比（HR）为5.79（95%CI：1.56~21.50；p=0.020），单个研究的效应量范围为1.58~22.04。但进一步分析显示，抗血管内皮生长因子（VEGF）治疗可缓解该耐药性，部分恢复ICI的治疗效果；在抗VEGF治疗队列中，高RER与不良生存的相关性未达到统计学意义（HR=3.39；95%CI：0.39~29.14；p=0.135）。
结论：据我们所知，本研究为首项评估Gd-EOB-DTPA增强MRI在HCC免疫治疗中预测价值的系统综述。研究结果表明，RER≥0.9可作为疗效不佳的潜在无创标志物。值得注意的是，抗VEGF联合治疗可缓解该影像学定义的耐药性这一发现具有假说生成价值，凸显了开展前瞻性研究以验证针对高RER肿瘤患者最优治疗策略的必要性。