Insulin-Like Growth Factor 2 Modulates Macrophage Polarization: the Role of the IGF2–IGFBP6 Axis

Triple-negative breast cancer (TNBC) is characterized by an aggressive clinical course and extremely limited targeted therapy options. One of the key drivers of immunosuppression in the tumor microenvironment is the polarization of tumor-associated macrophages (TAMs) towards the M2 phenotype. In the present study, we investigated the effect of insulin-like growth factor 2 (IGF2)-the primary ligand of the IGF1R receptor and a target of the inhibitory protein IGFBP6-on the transcriptional profile of macrophages polarized in vitro from the THP-1 cell line. We demonstrate that IGF2 exerts fundamentally different effects depending on the baseline functional state of the macrophages: in immature (M0) and M2-polarized cells, it induces the expression of pro-inflammatory genes, whereas in M1 macrophages it triggers pronounced immunosuppressive reprogramming. These findings suggest that IGFBP6, by inhibiting IGF2, may sustain an anti-tumor immune response within the TNBC microenvironment.