CD74 Drives M1 Macrophage Polarization via STAT3 Signaling to Promote Antitumor Immunity in Breast Cancer

Background: Immunosuppression contributes to breast cancer treatment failure, yet Cluster of Differentiation 74 (CD74) function in macrophages remains unclear. This study investigated how CD74 influences M1 macrophage polarization and its functional and expression profiles in breast cancer. Methods: We used bioinformatics analysis combined with in vitro cell experiments. The expression of CD74 in THP-1-derived M1 macrophages induced by Lipopolysaccharide/Interferon-gamma (LPS/IFN-γ) was knocked down by shRNA. Polarization markers were detected by WB, qPCR, and flow cytometry. Cytokines were detected by Enzyme-Linked Immunosorbent Assay (ELISA). The phagocytosis and killing effect of macrophages on MCF-7 cells were evaluated by a co-culture model combined with flow cytometry and Cell Counting Kit-8 (CCK-8). Results: CD74 is highly expressed in breast cancer and exerts a protective effect. Knocking down CD74 reduces the levels of M1 markers (iNOS, TNF-α) and inflammatory factors (TNF-α, IL-6), while simultaneously upregulating Signal Transducer and Activator of Transcription 3 (STAT3) tyrosine705 phosphorylation (p < 0.01). Functional experiments showed that CD74 deficiency impaired the ability of M1 macrophages to eliminate tumor cells via phagocytosis and induce tumor cell apoptosis (p < 0.05). Conclusions: CD74 has the potential to enhance macrophage immune function by inhibiting the STAT3 pathway and regulating M1 polarization. This offers a new perspective for researching the tumor immune microenvironment and presents CD74 as a potential target for breast cancer immunotherapy.