Hsu, Jung-MaoXia, WeiyaHsu, Yi-HsinChan, Li-ChuanYu, Wen-HsuanCha, Jong-HoChen, Chun-TeLiao, Hsin-WeiKuo, Chu-WeiKhoo, Kay-HooiHsu, Jennifer L.Li, Chia-WeiLim, Seung-OeChang, Shih-ShinChen, Yi-ChunRen, Guo-xinHung, Mien-Chie2018-06-272018Hsu, J., W. Xia, Y. Hsu, L. Chan, W. Yu, J. Cha, C. Chen, et al. 2018. “STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion.” Nature Communications 9 (1): 1908. doi:10.1038/s41467-018-04313-6. http://dx.doi.org/10.1038/s41467-018-04313-6.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160243Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that epithelial–mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal–epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.en-USJournal Article2018-06-2710.1038/s41467-018-04313-6