IL1RAP (interleukin-1 receptor accessory protein) functions as an essential coreceptor for IL-1, IL-33, and IL-36 signaling pathways 1. Unlike canonical IL-1 signaling, IL1RAP is required for Src phosphorylation by IL1B [UniProt reference]. The protein mediates inflammatory responses through positive regulation of MAPK cascades and NF-κB signal transduction [GO annotations]. Mechanistically, IL1RAP regulates multiple pathways: in Ewing sarcoma, it maintains redox homeostasis by enhancing cystine uptake and activating transsulfuration pathways for cysteine synthesis 2. In cardiovascular and fibrotic diseases, IL1RAP blockade reduces inflammatory cytokine production (IL-6, IL-8, MCP-1) and adhesion molecule expression in endothelial cells 3, while limiting leucocyte recruitment and plaque inflammation in atherosclerosis 4. Clinically, IL1RAP represents a promising therapeutic target across multiple malignancies and inflammatory diseases. IL1RAP is highly expressed on acute myeloid leukemia stem cells but not normal hematopoietic stem cells, enabling selective targeting via T cell engagers 5. Anti-IL1RAP antibodies show efficacy in systemic sclerosis-associated fibrosis 1, pancreatic cancer (median OS 13.2 months combined with chemotherapy) 6, and myocarditis by reducing cardiac inflammation and preserving function 7. These findings establish IL1RAP as a clinically actionable immunotherapeutic target.