IFI44 Orchestrates an IL-10–Driven M2 Macrophage Program in Breast Cancer: An Immune Prognostic Signature

Background: Although IFI44 is recognized for its crucial role in autoimmune disorders, its function in breast cancer (BC) remains unclear. This study aimed to investigate the immune-related and prognostic significance of IFI44 in BC. Methods: Bio-informatics analysis and in vitro experiments were performed to assess BC cells' proliferation, migration, and invasion. Immune cell infiltration was analyzed using CIBERSORT and ESTIMATE algorithms. The correlation between IFI44 and M2 macrophage markers was validated via TIMER2 and GEPIA2 databases. An IFI44-related M2 macrophage signature (IMS) was constructed using LASSO Cox regression. Its prognostic performance and association with immunotherapy/chemotherapy response were evaluated using survival analysis, ROC curves, and drug sensitivity data (GDSC2). Results: IFI44 was highly expressed in BC and associated with poor prognosis. Down-regulation of IFI44 BC cells inhibited M2 macrophages proliferation, but exogenous IL-10 in the knockdown-IFI44 BC cells rescued this reduction in vitro. The constructed IMS, based on four genes (GPR171, KIR2DS4, NPAS1, CD79A), effectively predicted the overall survival (OS) of BC patients with high specificity and sensitivity. Of note, the IMS was applied in pan-cancer and we found it could accurately predict the prognosis and immune score in multiple cancers. Conclusion: IFI44 promotes BC progression and M2 macrophage infiltration via an IL-10-mediated mechanism. IFI44 represents a promising target for immunotherapy in breast cancer. Our investigation identified that IFI44-based IMS provides a predictive scenario to determine the treatment and prognosis of cancer patients.