Abstract
BACKGROUND: Rechallenge with immune checkpoint inhibitors (ICIs) 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 are no standardized rechallenge regimen, 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 reexpression 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.