IGFBP3-mediated M2 Macrophage Polarization Enhances Resistance to Rosiglitazone and Cisplatin in Breast Cancer

Background Rosiglitazone (PPARγ agonist, RGZ) combined with chemotherapy drugs has proven effective in treating clinical breast cancer patients. However, the underlying targets and resistance mechanisms remain unclear, posing challenges in maintaining long-term efficacy. This study aimed to investigate the mechanisms of RGZ in macrophage polarization and evaluate its effects within the TME. Methods In vivo experiments were conducted using a patient-derived xenograft (PDX) nude mouse model resistant to chemotherapy, which simulates the clinical immune microenvironment. In vitro, the Thp-1 human monocytic cell line was induced to differentiate into macrophages and cocultured with MDA-MB-468 breast cancer cells. The effects of PPARγ agonists on the drug resistance of breast cancer cells in a coculture model were explored. Results An increase in M2 macrophages was observed in combination-resistant mice, with PPARγ activation by RGZ inducing macrophage differentiation toward the M2 phenotype. Knockdown of IGFBP3 in macrophages alleviated breast cancer cell resistance in the microenvironment by reversing polarization. Conclusion Our study revealed that targeting macrophage polarization through IGFBP3 can reverse the effects of PPARγ on macrophage polarization, promote cancer cell apoptosis and collectively reverse the resistance of tumor cells to combination therapy. These findings provide a new theoretical basis for anti-breast cancer treatment.