Pumping the brakes: immune checkpoints as regulators of immunity and targets of cancer therapy

Immunotherapy has become a mainstay of cancer treatment by enhancing the immune system's ability to recognize and eliminate tumors. The use of immune checkpoint inhibitors (ICIs) has significantly improved survival across a wide range of malignancies but also introduced a distinct category of toxicities. The immune activation triggered by ICIs is responsible for distinct immune-related adverse events (irAEs) ranging from mild, self-limited inflammation to severe, life-threatening organ damage. Here we provide an overview of the immunologic mechanisms and clinical features of irAEs. We discuss how the CTLA-4 and PD-1/PD-L1 immune checkpoints help maintain immune balance, and how their blockade results in unchecked immune activation. To place these observations in context, we compare irAEs with monogenic disorders of immune dysregulation affecting the same pathways to illustrate the overlapping pathogenic mechanisms. We review the presentation and immunopathology of organ-specific irAEs, and examine current approaches to clinical management, highlighting the use of targeted treatment approaches to control toxicity while preserving anti-tumor efficacy.