The omentum is the primary site of metastasis for ovarian cancer (OC). Interactions between cancer cells and adipocytes drive an invasive and pro-metastatic phenotype. Here we studied cancer cell-adipocyte crosstalk by using a direct co-culture model with immortalized human visceral pre-adipocytes (VNPAD) and OC cells. We demonstrate increased proliferation, invasiveness, and resistance to cisplatin of co-cultured compared to mono-cultured OC cells. RNA-sequencing of OC cells from co-culture vs. mono-culture revealed significant transcriptomic changes, identifying over 200 differentially expressed genes (DEGs) common to OVCAR5 and OVCAR8 cell lines. Enriched pathways included PI3K/AKT and Complement activation. Lipid transfer into OC cells from adipocytes induced upregulation of complement C3 and C5 proteins. Inhibiting C3 or C5 reversed the invasive phenotype and C3 knockdown reduced tumor progression in-vivo. Increased C3 expression was observed in omental implants compared to primary ovarian tumors and C3 secretion was higher in OC ascites from high BMI vs. low BMI patients. C3 upregulation in OC cells involved activation of ATF4-mediated integrated stress response (ISR). Overall, adipocyte-cancer cell interactions promote invasiveness and tumorigenesis via lipid transfer, activating ISR, and upregulating complement proteins C3 and C5.