Wei Guo, Ziyi Li, Qihan Chen, Garett Dunsmore, Li Jiang, Zhijie An, Ziwen Fu, Yibo Liu, Yufei Shao, Shulin Zhao, Ting Wang, Huan Tang, Chengjian Zhao, Guangyan Zhangyuan, Jia Liu, Pengyi Liu, Zhaoyuan Liu, Jiawen Qian, Shuangyan Zhang, Minmin Shi, Ding He, Yedan Liu, Camille Blériot, Lai Guan Ng, Fan Bai, Lingxi Jiang, Bing Su, Baiyong Shen, Florent Ginhoux
Pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer with a poor prognosis, contains resident tissue macrophages (RTMs) present before tumor onset and monocyte-derived macrophages recruited during tumor development, but their distinct roles in supporting tumor progression remain unclear. Combining single-cell profiling, spatial analysis, lineage tracing, RTM depletion, and selenium tracing, we found that RTMs preferentially localize at the tumor border, where they promote epithelial-mesenchymal transition (EMT), tumor growth, and metastasis. Mechanistically, RTMs transfer the selenium transporter Selenop to EMThi tumor cells through LRP8-dependent uptake, increasing tumor-cell selenium availability, limiting lipid peroxidation, and shielding EMThi tumor cells from ferroptosis. RTM-specific Selenop deletion or tumor-cell Lrp8 disruption reduced EMT and tumor progression, whereas ferroptosis inhibition reversed the effect of RTM depletion. Human PDAC showed border-enriched SEPP1+ RTMs near EMThi tumor cells, suggesting a conserved macrophage-derived selenium niche that supports invasive tumor states and highlighting the potential for targeting RTMs or their secretory factors in PDAC.