Background <p>FOXL2, a key regulator of ovarian development, is linked to ovarian disorders, but its role in epithelial ovarian cancer (EOC) remains unclear. EOC progression is driven by cancer-associated fibroblasts (CAFs), and our data show FOXL2-expressing CAFs in EOC correlate with poor prognosis (high grade, lymphatic metastasis, advanced stage).</p> Methods and results <p>Primary CAFs were isolated from 10 patient EOC tissues via collagenase/hyaluronidase digestion. Experiments used these CAFs and A2780 cells, with in vitro assays in 3 replicates and in vivo studies with 5 mice/group. String analysis predicted a strong FOXL2-SUMO1 interaction, validated by Ni2⁺ NTA pull-down showing SUMO1 as the primary FOXL2 modifier (higher than SUMO2/3, <i>p</i> &lt; 0.001). UBC9 enhanced FOXL2 SUMOylation (indicating UBC9 dependence), and SUMOylation stabilized FOXL2 by reducing ubiquitination. SUMOylated FOXL2 in CAFs promoted EOC cell proliferation, invasion, and migration. FOXL2 + CAFs activated TGF-β/Smad signaling via TGF-β secretion, and the inhibitor SB431542 reduced in vivo tumor growth induced by A2780 cells and FOXL2 + CAFs.</p> Conclusion <p>Our results cumulatively indicate that FOXL2 SUMOylation can maintain the FOXL2 stability in CAFs, thus accelerating tumorigenesis in ovarian cancer.</p> Clinical trial number <p>Not applicable.</p>