Zeynep Akçor, Melisa Ekici, Yasin Kaymaz
Experimental Biomedical Research - 2026;9(1):50-67
Aim: To investigate transcription factor regulons that drive macrophage polarization across multiple cancer types using single-cell RNA sequencing data. Method: Publicly available datasets from lung, ovarian, pancreatic, and head and neck cancers were retrieved. After standard quality control and normalization, gene regulatory networks were reconstructed using a bioinformatic workflow that integrates co-expression analysis, motif enrichment, and regulon activity scoring. Transcription factors associated with M1 and M2 macrophage polarization were systematically examined. Results: Analysis of regulon activity revealed that macrophages in lung, ovarian, and pancreatic cancers predominantly exhibited M1-associated transcriptional programs, suggesting anti-tumor properties. Key active transcription factors in these cancers included JUND, STAT1, NFkappaB, and IRF1. In contrast, head and neck cancers displayed a predominance of M2-associated transcriptional activity, with strong enrichment of SPI1, CEBPB, and IRF8, indicative of pro-tumor macrophage polarization. Conclusions: This study demonstrates that transcription factor regulon analysis can distinguish tumor-associated macrophage states across cancers and provides insights into their divergent roles in tumor progression. The identification of cancer type-specific transcriptional drivers of macrophage polarization may inform the development of macrophage-targeted immunotherapies and improve prognostic biomarker discovery.
