YTHDF2 favors protumoral macrophage polarization and implies poor survival outcomes in triple negative breast cancer

Highlights•m6A reader YTHDF2 was highly expressed in pro-tumoral macrophages•YTHDF2 correlates with pro-tumoral and immuno-suppressing signals of macrophages•Identification of SPI1 as key transcriptional regulator in YTHDF2-high macrophage•Ythdf2 associates with pro-tumoral phenotype polarization of macrophages in the miceSummaryPatients with triple-negative breast cancer (TNBC) frequently experience resistance to chemotherapy, leading to recurrence. The approach of optimizing anti-tumoral immunological effect is promising in overcoming such resistance, given the heterogeneity and lack of biomarkers in TNBC. In this study, we focused on YTHDF2, an N6-methyladenosine (m6A) RNA-reader protein, in macrophages, one of the most abundant intra-tumoral immune cells. Using single-cell sequencing and ex vivo experiments, we discovered that YTHDF2 significantly promotes pro-tumoral phenotype polarization of macrophages and is closely associated with down-regulated antigen-presentation signaling to other immune cells in TNBC. The in vitro deprivation of YTHDF2 favors anti-tumoral effect. Expressions of multiple transcription factors, especially SPI1, were consistently observed in YTHDF2-high macrophages, providing potential therapeutic targets for new strategies. In conclusion, YTHDF2 in macrophages appears to promote pro-tumoral effects while suppressing immune activity, indicating the treatment targeting YTHDF2 or its transcription factors could be a promising strategy for chemoresistant TNBC.