SYSTEMATIC REVIEW article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
Advancing Immune Checkpoint Inhibitor Rechallenge: Key Insights into Efficacy, Safety, and Personalized Strategies in Advanced Solid Tumors
Provisionally accepted
ShiFen Lu*
Zhong XIE- Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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ICIs have radically altered the treatment of solid tumors at an advanced stage. However, the discontinuation of the therapy as a result of primary/acquired resistance or intense immune-related adverse events (irAEs) is still a serious problem. Reintroduction of ICIs recently, known as immune checkpoint inhibitor rechallenge, is a promising but complicated approach to treatment that is currently not providing any standardized guidelines. The review is a synthesis of the existing evidence on ICI rechallenge, which includes an in-depth analysis of patient selection, an ideal time, optimal methods of therapy, and safety management. The key predictors of successful rechallenge identified in our findings include a lasting response to initial ICI therapy (progression-free survival [PFS1] 6 months and preferably 12 months), a long treatment-free interval (TFI 6 months) good baseline-level performance status (ECOG-PS ≤1), and the absence of previous irAEs (symptoms resolving to grade ≤1). The objective response rates can be improved by combination therapy to chemotherapy, anti-angiogenic therapy, or local radiotherapy, which can positively adjust the tumor microenvironment. Nonetheless, the recurrence of irAEs after rechallenge is still a significant issue (20-60% reported rates), which often requires the irreversible discontinuation after severe toxicity. The purpose of the review is to provide clinicians with evidence-based recommendations on making individual decisions contributing to effective management by focusing on the assessment of the patient in full and multidisciplinary management. The future research needs are to define specific dynamic biomarkers, investigate new combination therapies to overcome the various resistance mechanisms, and define the best time to rechallenge to standardize and personalize ICI rechallenge in clinical practice.
Keywords: Advanced solid tumors, biomarkers, ICI Rechallenge, immune checkpoint inhibitors, Immune-related adverse events, prognostic factors, Safety Management, treatment strategies
Received: 13 Dec 2025; Accepted: 16 Feb 2026.
Copyright: © 2026 Lu and XIE. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: ShiFen Lu
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