The immune system protects the host from non-self, i.e. foreign invaders and malignant cells, while seeking to minimize damage to healthy cells. This delicate balance between immune activation and tolerance, commonly referred to as immunologic homoeostasis, is crucial to ensure life. Immune checkpoints (ICs) play a pivotal role in maintaining this balance. Specifically, inhibitory ICs such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3), downregulate an immune response to avoid off-target organ damage.

Tumours, however, hijack this physiological mechanism to evade the immune system. Through the upregulation of inhibitory ICs in the tumour micro-environment, they protect themselves against anti-tumour responses, allowing for cancer survival and progression. Immune checkpoint inhibitors (ICIs) have therefore been developed to boost anti-tumour immunity, with great clinical success. As of 2022, anti-CTLA-4, anti-PD-1, its ligand anti-programmed death-ligand 1 (anti-PD-L1) as well as anti-LAG-3 treatment have been approved for clinical use. As can be anticipated from their mechanism of action, the increasing use of ICIs also results in a growing number of patients who suffer from immune reactions against normal tissues, termed immune-related adverse events (irAEs). These toxicities can affect virtually every organ in the body, often necessitating ICI treatment interruption or discontinuation and immunosuppressive treatment. irAEs severely reduce quality of life and can even result fatal. Despite their clear impact on patient care, many aspects of irAEs remain elusive. What are the precise mechanisms by which ICs maintain immune tolerance, and conversely, what happens at the molecular level when an irAE develops? Should irAEs be regarded as ICI-triggered counterpart of a spontaneous autoimmune disease, or are these entities distinct? Alternatively, are irAEs mechanistically identical to the anti-tumour immune response or not (and if not, can irAEs be selectively targeted)? Finally, why do some patients develop irAEs and others do not?

In this narrative review, we first summarize the biology of IC deficiency and clinical features of irAEs. Next, we critically discuss existing knowledge on the mechanisms and predisposing factors of irAEs. Finally, we comment on how this knowledge is currently reshaping the treatment landscape of irAEs, and how it might revolutionize ICI therapy in the future.