S100A14 in Tumor‐Derived EVs Targets PIAS3 to Reprogram Astrocytes and Induce Immunosuppressive Microenvironment Promoting Brain Metastasis and Germacrone Reversal Effect

Brain metastasis (BrM) is the most common complication with the highest mortality in clinical tumor patients. 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-derived exosomes (EVs)-driven BrM. DIA-based proteomics demonstrated consistently high S100A14 expression in BrM-EVs from both cells (53.2-fold in A549 BM3 cells and 2.4-fold in 4T1 BM2 cells) and clinical patient samples (5.1-fold). Intracardiac injection mice model confirmed that S100A14-overexpression EVs promoted BrM in breast (4T1: 88.89% vs. 44.45%; MDA-MB-231: 66.67% vs. 33.33%) and lung cancer (LLC: 50% vs. 33.33%; A549: 83.33% vs. 33.33%). Mechanistically, S100A14 directly targeted PIAS3 to reprogram astrocytes (AS) by activating STAT3 signaling and triggering secretion of pro-inflammatory 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-PIAS3 interaction, inhibit STAT3 activation, and MDSCs recruitment. Our study elucidated a novel mechanism by which tumor-derived S100A14 EVs promote tumor BrM. Moreover, germacrone emerged as a prospective therapeutic agent for preventing BrM by specifically targeting S100A14.