High-grade serous ovarian cancer (HGSOC) is a major cause of death among women worldwide and effective HGSOC therapeutic strategies remain an unmet medical need. Cancer-associated mesenchymal stem cells (CA-MSCs) are epigenetically reprogrammed and gain a pro-tumorigenic function in HGSOC patients. Loss of CA-MSCs signature is significantly correlated with patient survival improvement. Wilm’s tumor 1 (WT1) is a transcriptional factor and its overexpression functionally drives the tumor-promoting function of CA-MSCs and promotes therapy resistance. Hence, we utilized WT1 as a functional readout and performed a CRISPR screening to unbiasedly identify epigenetic targets that promote the pro-tumorigenic function of CA-MSCs. My epigenetic CRISPR screening presents YEATS2 as the top-ranked significant activator of WT1 expression in HGSOC CA-MSCs. Notably, small molecule inhibitors of YEATS2 have been developed targeting its YEATS domain. Moreover, YEATS2 depletion significantly suppresses the pro-tumorigenic function of CA-MSCs. Mechanistically, YEATS2 promotes the pro-tumorigenic function of CA-MSCs by enforcing the WT1-Interferon regulatory factor (IRF)-type I interferon (IFN) signaling axis. Indeed, the gain of CA-MSC signature led to a decreased expression of markers of cytotoxic effector CD8 T and NK cells, such as PRF1 and GZMB. Thus, this work may present YEATS2 as a promising therapeutic target to suppress the tumor-promoting function of CA-MSCs.