Available online 16 April 2025, 101625

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This manuscript delves into our current understanding of cytokines and how they are implicated in the development of immunotherapy related adverse events (irAEs.) It highlights our current understanding, future directions and potential pitfalls of targeting cytokines for irAE management and prophylaxis.

Abstract:

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.

Section snippetsIntroduction:

Since their initial introduction into clinical practice, immune checkpoint inhibitors (ICIs) that target the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death receptor-1 and its ligand (PD-(L)1), and lymphocyte activation gene-3 (LAG-3) have revolutionized the oncology treatment landscape. ICIs are approved for more than 20 different solid tumor types, several hematologic malignancies, and tumors with high tumor mutational burden and microsatellite instability, regardless

Conclusion:

Over the past fourteen years, the era of immune checkpoint inhibition has revolutionized cancer treatment, giving rise to clinicians more familiar with diagnosing and managing these irAEs. However, despite growing clinical experience with these therapies, numerous unanswered questions exist regarding the optimal management of these adverse events. Retrospective data has shown that steroid usage can have detrimental effects on the efficacy of ICI therapy. This is best explained by the broad

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