A novel metabolic regulatory mechanism of ovarian cancer by omentum adipose-derived stroma cells (O-ASCs) has been discovered. O-ASCs induce survival, migration, and chemoresistance of ovarian cancer cells. However, the underpinning mechanism behind the metabolic modulation was not understood. Here, O-ASCs are shown to promote nitric oxide (NO) homeostasis in ovarian cancers by generating the pool of arginine. Ovarian cancer cells benefit from tumor microenvironment’s elements and expand their growth. In turn, cancer cells modify the elements’ fate to further take advantage of nutrients and resources. A unique combinatory drug treatment is proposed to target O-ASCs-induced chemoresistance of ovarian cancer cells.