When Checkpoint Inhibitors Break Barriers: Mechanisms and Challenges of irAEs of the Skin, Gastrointestinal Tract, and Lung

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, although their use is limited by immune-related adverse events (irAE)-off-target immune responses that can affect any organ, frequently lead to ICI discontinuation, and require immunosuppressive therapy. Barrier organs, including the skin, gastrointestinal tract, and lung, are among the tissues most frequently affected by irAEs. As barrier organs, these tissues share important functions in maintaining separation from the external environment, participating in gas and nutrient exchange, and initiating localized immune responses that balance protection with tolerance. In this review, we highlight common immunologic features of these barrier organs and how they contribute to the immunopathogenesis of tissue-specific irAEs. We specifically review the contribution of T lymphocytes, myeloid cells, interferons, interleukins, androgens, autoantibodies, oxygenation, and dysbiosis to irAE pathogenesis. Finally, we identify gaps in the understanding of shared immunologic mechanisms across barrier irAEs and highlight how an interdisciplinary approach to irAE treatment would improve the survival and quality of life of patients with cancer.