IRAK signaling in cancers: mechanisms, targeting, and clinical implications

All human cells have the capacity to respond to damage or danger through conserved signaling pathways that converge on interleukin-1 receptor-associated kinases (IRAKs). IRAKs are a family of kinases that play central roles in innate immunity and inflammation and are increasingly implicated in the development and progression of cancer.

IRAKs are tightly regulated by multiple mechanisms to prevent aberrant activation. Dysregulated IRAK function has been increasingly recognized for its role in cancer initiation, progression, and therapy resistance, extending beyond its canonical function in inflammatory signaling. While much of the research to date has focused on IRAK signaling in hematologic malignancies, emerging evidence suggests that IRAKs are also activated and therapeutically relevant in solid tumors. As a result, several small-molecule inhibitors targeting one or more IRAK family members are now approved, in clinical trials, or under preclinical development. In this review, we summarize the current understanding of IRAK biology in cancer, with a particular focus on therapeutic strategies and the translational potential of IRAK-targeted therapies.

IRAK inhibitors and degraders are promising treatments for a variety of cancers. Future clinical success will depend on optimizing kinase selectivity profiles and identifying biomarkers to guide patient selection and combination strategies.