ABSTRACT Despite the pivotal role of tumor immune microenvironment (TIME) in breast cancer (BC) progression, the functional contributions of mast cells (MCs) within the TIME remain poorly understood. Utilizing single‐cell RNA sequencing on tumor (T) and adjacent para‐tumor (PT) tissues from BC patients, we identified a distinct transcriptional profile in T‐derived tumor‐resident MCs (MCt) compared to their PT counterparts. Survival analysis revealed that MCt signature gene set significantly correlated with poor clinical outcomes. To assess functional roles, we established in vitro co‐culture systems and in vivo murine allograft models, which demonstrated that MCt promoted BC cell proliferation and enriched ALDH + breast cancer stem cells (BCSCs). Mechanistically, through molecular inhibitors, agonist, recombinant protein, and gene‐knockdown cell lines, we found that MCt‐derived IFNB1 activated the Type I interferon pathway in BC cells via the IFNAR1‐STAT1 axis. Reciprocally, BC cells upregulated IFNB1 expression in MCs via stem cell factor (SCF)‐mediated c‐KIT‐MAPK/ERK signaling. This bidirectional crosstalk established a self‐reinforcing IFNB1/SCF feedforward loop driving BC progression and stemness, which was further validated in BC patient tissues by multiplex immunohistochemistry. Collectively, our findings characterize a pro‐tumorigenic MC subset within the TIME and propose a potential novel therapeutic strategy for BC by disrupting the MCt‐BC cell interplay.
Li et al. (Mon,) studied this question.