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

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.

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.

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.