Defining the role of IL1RAP as a therapeutic target in triple negative breast cancer

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide, with triple-negative breast cancer (TNBC) representing a particularly aggressive subtype lacking effective targeted therapies. This thesis investigates the role of interleukin-1 receptor accessory protein (IL1RAP), a key mediator of IL-1 signaling, in TNBC progression and its potential as a therapeutic target. Bioinformatic analyses revealed that IL1RAP is significantly overexpressed in TNBC and is associated with poor prognosis, inflammatory signaling, cancer-associated fibroblasts, and myeloid cell infiltration. Mechanistic studies demonstrated that IL-1 signaling promotes a pro-inflammatory phenotype in TNBC cells, CAFs and cooperates with the Oncostatin M (OSM) pathway to reinforce tumor-promoting inflammatory networks. Importantly, targeting IL1RAP with the therapeutic antibody Nadunolimab reduced TNBC cell proliferation and invasion in vitro, inhibited tumor growth in an TNBC in ovo model, and delayed tumor re-growth when combined with chemotherapy in an immunodeficient TNBC mouse model. Together, these findings identify IL1RAP as a central regulator of inflammatory processes within the TNBC tumor microenvironment and support its further clinical development as a promising therapeutic target for this challenging breast cancer subtype.