IFN-γ-STAT1 Axis Drives MHC-II Antigen Presentation Potentiation in Tumor Associated Macrophages

While the IFN-γ-STAT1 signaling pathway is well-characterized in promoting MHC class II (MHC-II)-dependent antigen presentation within pro-inflammatory macrophages during acute infections, its functional dynamics in tumor-associated macrophages (TAMs) remain poorly understood. Here, we systematically investigated the immunomodulatory role of IFN-γ-STAT1 axis in TAMs through integrative bioinformatics and experimental validation. Transcriptomic analysis of tumor-infiltrating myeloid cells across multiple cancer cohorts revealed a strong correlation between STAT1 activation and MHC-II pathway enrichment, particularly in IFN-γ-high TAM subsets. To mechanistically dissect this relationship, we employed bone marrow-derived macrophages (BMDMs) polarized under tumor-conditioned media and subjected them to IFN-γ stimulation. Single-cell RNA sequencing demonstrated that IFN-γ triggered STAT1 nuclear translocation, upregulating MHC-II genes. Our findings establish IFN-γ-STAT1 as a master regulator of TAM immunogenicity, proposing targeted STAT1 activation as a strategy to overcome myeloid-driven immunosuppression in cancer.