Integrated Single-Cell Analysis Identifies IL1RAP as a Master Regulator of TAMs and a Prognostic Biomarker in Breast Cancer

The recruitment and polarization of tumor-associated macrophages (TAMs) play a pivotal role in shaping the immunosuppressive tumor microenvironment in breast cancer. Interleukin-1 receptor accessory protein (IL1RAP), a critical co-receptor for IL-1 family cytokines, is emerging as a potential regulator of macrophage function, though its specific role in TAM biology remains to be explained. In this study, we investigated the impact of IL1RAP on macrophage recruitment and M2-like polarization. Initial bioinformatics analysis of public databases revealed a significant correlation between elevated IL1RAP expression in macrophages and signatures of immune suppression and poor prognosis in breast cancer. To functionally validate these findings, we performed IL1RAP knockdown in a murine macrophage cell line. Our results demonstrated that IL1RAP deficiency markedly impaired the migratory capacity of macrophages towards classic chemotactic stimuli. Furthermore, under M2-polarizing conditions, IL1RAP-knockdown macrophages exhibited a significantly attenuated M2 phenotype, as evidenced by the decreased expression of canonical M2 markers (e.g., Arg1, Mrc1) and reduced functional outputs. Collectively, our integrated approach combining bioinformatics and in vitro experimentation identifies IL1RAP as a novel regulator that potentiates both the recruitment and the M2 polarization of macrophages. These findings suggest that targeting the IL1RAP pathway could represent a promising therapeutic strategy for reprogramming the tumor-immune microenvironment by limiting pro-tumoral macrophage infiltration and polarization.