Refractory immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy: a multiorgan management review

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have transformed the treatment of multiple malignancies and significantly increased survival; however, by enhancing antitumor immunity, they can also cause off-target immune-related adverse events (irAEs), some of which become refractory to standard first-line corticosteroids. Refractory irAEs (r-irAEs) require timely recognition and personalized, organ-specific escalation strategies based on toxicity severity and mechanistic insights. AREAS COVERED: In this narrative review, we synthesize current evidence across organ systems on the epidemiology, clinical features, diagnostic evaluation, and management of r-irAEs, with a particular focus on second- and third-line immunosuppressive options. We summarize findings from retrospective cohorts, prospective studies, guideline statements, and high-quality case series relevant to steroid-refractory irAEs and highlight practical considerations for escalation. The literature search was performed in PubMed and Embase for publications from January 2010 through August 2025. EXPERT OPINION: Tailored treatment strategies and structured escalation algorithms are needed to optimize outcomes for patients with r-irAEs. Integration of emerging biomarkers, endoscopic and histologic findings, and tumor microenvironment features may facilitate earlier recognition of steroid-refractory disease and more individualized escalation of immunosuppression.