Epithelial ovarian cancer (EOC) is characterized by a highly immunosuppressive tumor microenvironment (TME) that enables EOC progression and limits the efficacy of current immunotherapies. In this study, we demonstrated that isogenic BRCA2-mutated PEO1 and BRCA2-wild type PEO4 EOC cells induced immunosuppressive TMEs through distinct mechanisms. PEO1 cells produced IFNγ-induced PD-L1 and expressed CD39 and CD73 for generating adenosine. Treatment with the adenosine antagonist CGS15943 reversed PEO1 cell-mediated suppression of effector T cell activation. In contrast, PEO4 cells secreted IFNγ-induced CXCL10 and promoted up-regulation of FOXP3+ regulatory T cells (Tregs). Treatment with the CXCL10/CXCR3 antagonist AMG487 attenuated PEO4 cell-induced Tregs and decreased IL10 production. In vivo, administration of a monoclonal antibody against CXCR3 effectively hindered the progression of tumor ascites and prolonged survival in the p53(-/-) ID8 EOC syngeneic mouse model. Additionally, AMG487 treatment synergized with the VEGFA inhibitor bevacizumab, significantly reducing tumor ascites and extending mouse survival. Collectively, our results reveal that EOC leverages CXCL10-induced Tregs or adenosine signaling to dampen T cell-mediated anti-cancer immune responses. These findings suggest that targeting CXCL10/CXCR3 and adenosine signaling could effectively counter immunosuppression of EOC, offering a promising therapeutic strategy for improving patient outcomes.