Gastrointestinal immune-related adverse events from immune checkpoint inhibitors: an evidence-informed, phenotype-directed framework for selective immunosuppression and rechallenge

Gastrointestinal immune-related adverse events (GI-irAEs) are among the most consequential toxicities of immune checkpoint inhibitors. Their spectrum extends from histological inflammation beneath normal-appearing mucosa to fulminant enterocolitis. Management is difficult because stool-frequency grade incompletely represents mucosal injury, several infectious and non-immune disorders mimic immune-mediated disease, and treatment sequencing rests largely on guidelines and observational evidence. This Review integrates current guidance, including the transition to Common Terminology Criteria for Adverse Events version 6.0, with endoscopic, histological, microbiome, single-cell and spatial evidence. We frame GI-irAEs as multidimensional mucosal syndromes defined by anatomical site, inflammatory phenotype, physiological or structural risk, and treatment trajectory. The framework informs care but is neither a validated score nor a guideline. Budesonide may be considered in selected stable patients with biopsy-defined microscopic-colitis-like disease, based on small, non-randomised evidence. By contrast, macroscopic ulceration or physiological compromise warrants early systemic treatment and planning for selective immunosuppression. Upper-GI, small-bowel and chronic active/IBD-like phenotypes require site-specific investigation and follow-up. Infliximab and vedolizumab remain the best-supported selective immunosuppressive options, although non-randomised comparisons establish no universal preference. Concurrent selective immunosuppression during rechallenge after biologic-requiring enterocolitis is an emerging retrospective strategy; faecal microbiota transplantation, ustekinumab and Janus-kinase inhibitors remain experimental rescue approaches. The clinical priority is to recognise high-risk mucosal disease early, limit ineffective corticosteroid exposure, document recovery and treat rechallenge as a renewed multidisciplinary oncological benefit–risk decision.