Supplementary Material for: Rechallenge with immune checkpoint inhibitors in patients with hepatocellular carcinoma: a narrative review

Background: Rechallenge with immune checkpoint inhibitors (ICI) has recently emerged as a potential therapeutic strategy for patients with hepatocellular carcinoma (HCC) who discontinue initial immunotherapy due to disease progression, immune-related adverse events (irAEs), or treatment completion. However, there is no standardized rechallenge regimens, patient indications, and few studies on its mechanism.
Summary: This review provided a comprehensive, up-to-date summary on the clinical evidence, treatment regimens, patient characteristics, and biological rationale underlying ICI rechallenge for HCC patients. Current studies have identified four main rechallenge strategies according to the combinations of agents used in the initial and rechallenge treatments, most of which involve targeted therapy combined with anti-PD-L1 or dual ICIs. Across published studies, ICI rechallenge has shown variable but notable antitumor activity with an acceptable safety profile. Clinical benefits appear to be more frequently observed in HCC patients with preserved liver function, age < 60 years, and lower tumor burden, although these findings require cautious interpretation due to interstudy heterogeneity and potential selection bias. Mechanistic investigations suggest that renewed immune activation may result from immunogenic cell death, tumor microenvironment remodeling, and re-expression of inhibitory checkpoints such as PD-L1 or CTLA-4, thereby restoring antitumor immunity.
Key Messages: ICI rechallenge represents a rational and feasible therapeutic option for selected HCC patients, providing an opportunity to achieve additional clinical benefit after initial ICI resistance or discontinuation. Although the frequency of irAEs may increase, most events remain manageable with vigilant monitoring and timely intervention. Future research should focus on optimizing regimen selection, refining predictive biomarkers, and elucidating the molecular basis of immune reactivation to guide individualized ICI rechallenge strategies and expand their clinical applicability.

背景：针对因疾病进展、免疫相关不良事件（immune-related adverse events, irAEs）或治疗完成而终止初始免疫治疗的肝细胞癌（hepatocellular carcinoma, HCC）患者，免疫检查点抑制剂（immune checkpoint inhibitors, ICI）再挑战疗法近期已成为一种潜在治疗策略。然而，目前尚无标准化的再挑战治疗方案与患者适应证，且相关作用机制研究较为匮乏。
摘要：本综述针对HCC患者接受ICI再挑战治疗的临床证据、治疗方案、患者特征及生物学机制，提供了全面且最新的总结。现有研究根据初始治疗与再挑战治疗的药物组合模式，明确了四大主要再挑战策略，其中多数方案为靶向治疗联合抗PD-L1治疗或双重ICI治疗。已发表研究显示，ICI再挑战治疗展现出程度不一但值得关注的抗肿瘤活性，且安全性良好。临床获益更常见于肝功能保留良好、年龄＜60岁且肿瘤负荷较低的HCC患者，但由于研究间异质性与潜在选择偏倚，上述结论需谨慎解读。机制研究表明，免疫原性细胞死亡、肿瘤微环境重塑以及PD-L1或CTLA-4等抑制性检查点的重新表达，可能介导了免疫激活的恢复，从而重建抗肿瘤免疫。
核心要点：ICI再挑战疗法对于经过筛选的HCC患者而言，是一种合理且可行的治疗选择，为初始ICI治疗耐药或终止治疗的患者提供了获得额外临床获益的机会。尽管irAEs的发生频率可能升高，但多数不良事件可通过严密监测与及时干预得到有效管控。未来研究应聚焦于优化方案选择、筛选预测性生物标志物，以及阐明免疫再激活的分子机制，以指导个体化ICI再挑战策略的制定，并拓展其临床应用范围。