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Its underlying pathogenesis remains unclear, and effective therapeutic compounds are currently unavailable. Herein, we first revealed that S100A14 is a critical molecular mediator of tumor\u2010derived exosomes (EVs)\u2010driven BrM. DIA\u2010based proteomics demonstrated consistently high S100A14 expression in BrM\u2010EVs from both cells (53.2\u2010fold in A549 BM3 cells and 2.4\u2010fold in 4T1 BM2 cells) and clinical patient samples (5.1\u2010fold). Intracardiac injection mice model confirmed that S100A14\u2010overexpression EVs promoted BrM in breast (4T1: 88.89%\u00a0vs. 44.45%; MDA\u2010MB\u2010231: 66.67%\u00a0vs. 33.33%) and lung cancer (LLC: 50%\u00a0vs. 33.33%; A549: 83.33%\u00a0vs. 33.33%). Mechanistically, S100A14 directly targeted PIAS3 to reprogram astrocytes (AS) by activating STAT3 signaling and triggering secretion of pro\u2010inflammatory chemokines (CCL2\/CCL5\/CXCL5), which recruit immunosuppressive MDSCs. Crucially, we identified the natural compound, germacrone, as a promising therapeutic agent that effectively inhibited BrM progression in both lung and breast cancer without significant toxicity. Germacrone directly binds to S100A14 in AS to disrupt the S100A14\u2010PIAS3 interaction, inhibit STAT3 activation, and MDSCs recruitment. Our study elucidated a novel mechanism by which tumor\u2010derived S100A14 EVs promote tumor BrM. Moreover, germacrone emerged as a prospective therapeutic agent for preventing BrM by specifically targeting S100A14.<\/jats:p>","DOI":"10.1002\/advs.202522921","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T15:18:53Z","timestamp":1775834333000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["S100A14 in Tumor\u2010Derived EVs Targets PIAS3 to Reprogram Astrocytes and Induce Immunosuppressive Microenvironment Promoting Brain Metastasis and Germacrone Reversal Effect"],"prefix":"10.1002","volume":"13","author":[{"given":"Qian","family":"Feng","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Translational Chinese Medicine, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines International Institute for Translational Chinese Medicine School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine 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