The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T-lymphocyte antigen-4 and programmed death-1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune-related adverse events (irAEs), ranging from mild to life-threatening. Several publications have addressed the clinical and histopathological classification of these skin-directed irAEs, their impact on anti-tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune-related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment-related reactions. We detail the specific immune-based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune-related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood-based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic-based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti-tumour effect of ICIs.
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