Advancing immune checkpoint inhibitor rechallenge: key insights into efficacy, safety, and personalized strategies in advanced solid tumors

Introduction: Immune checkpoint inhibitors (ICIs) have turned out to be a potent treatment of advanced solid tumor, but the issue of therapy discontinuation under the influence of the resistance, or immune-related adverse events (irAEs) is still a significant challenge. ICI rechallenge, which is a reintroduction of immunotherapy after initial failure is a favorable alternative whose guidelines are not standardized. Methods: This narrative review was a literature synthesis of the existing evidence drawn from PubMed, Web of Science, Embase, and Cochrane Library as up to July 21, 2025. We assesed real-world studies, retrospective cohorts, and meta-analyses, which examined patient selection criteria, rechallenge strategies, efficacy results, and safety profile across different types of solid tumors. Findings: The predictors of successful rechallenge include persistent initial response (progression-free survival ≥6 months), prolonged treatment-free interval (≥6 months), excellent performance status (ECOG-PS ≤1), and complete irAE resolution (Grade ≤1). The outcome of an after toxicity rechallage is superior to after progression (median PFS: 5.1 vs. 2.9 months). There is a better response to a combination of anti-angiogenics, chemotherapy, or radiotherapy strategies. However, the recurrence rate of irAE is 20%-60% and severe initial toxicities can be a reason to discontinue the drug permanently. Discussion: ICI rechallenge benefits the right patients significantly. We propose a clinical decision model that might assist in integrating both biological and clinical variables to base individualized rechallenge, but the standard set of criteria and possibilities to validate biomarkers remains in urgent need.