Precision immunomodulation: Understanding and harnessing cytokine pathways to treat and prevent immune-related adverse events (irAEs)

The utilization of immune checkpoint inhibitors has fundamentally changed both the treatment landscape for a multitude of malignancies as well as our understanding of cancer biology. Despite profound advancements, the utilization of these drugs is often limited by the development of immune-related adverse events (irAEs), characterized by off-target toxicity to healthy tissue secondary to treatment. Currently, irAEs are often treated with high-dose corticosteroids, with additional immunosuppressive agents added for severe or refractory irAEs. Cytokine pathway inhibitors, particularly anti-TNFa and anti-IL-6R antibodies, are commonly used as second-line immunosuppression. The efficacy of blocking these pathways in treating irAEs, as well as their potential impact on anti-tumor response, will be discussed. Additionally, this review will also explore other cytokines implicated in irAE pathophysiology, including interleukin-17 (IL-17), interleukin-23 (IL-23), interleukin-4/13 (IL-4/IL-13) and interleukin-5 (IL-5) which play important roles in the inflammatory cascades underlying specific irAEs such as colitis, dermatitis, and eosinophilia-related toxicities.