Objectives: The diversity of tumor-associated macrophages (TAMs) is known to contribute to adaptive resistance to anti-VEGF therapy in ovarian cancer. CCR2+ macrophages are thought to have immunosuppressive effects and contribute to immune evasion through the CCL2-CCR2 axis. MSMP (a novel CCR2 ligand)/CCR2 axis plays an important role in promoting adaptive resistance in ovarian cancer models. Here, we examined the effects of BET inhibitors (BETis) (e.g., ABBV-075, CPI 203, and JQ1) on MSMP/CCR2 axis and CCR2+ TAMs in ovarian cancer resistant to anti-VEGF therapy. Methods: We used the TIMER and CIBERSORT analytical tools for estimating the associations between macrophages and CCR2 or clinical associations in ovarian cancer. We also carried out a series of in vitro (chemotaxis, apoptosis, flow cytometry, and RNA sequencing) and in vivo (adaptive resistant model of SKOV3ip1 ovarian cancer) experiments to determine the effects of BETis on the MSMP/CCR2 axis and overcoming resistance to bevacizumab in ovarian cancer. Results: CIBERSORT database revealed that high M1-like macrophages (tumoricidal) were associated with better overall survival of patients with ovarian cancer, while high M2-like macrophages (pro-tumoral) were associated with poor overall survival (p<0.01). TIMER analysis further revealed that CCR2 expression was significantly associated with monocyte and macrophage infiltration in ovarian cancer (p<0.01). To search druggable transcriptional factors of MSMP and CCR2, we used the transcriptomic database and western blot analyses and identified that BETi decreased MSMP expression in cancer cells and CCR2 in monocytes/macrophages, likely in a BRD4-dependent manner. In vitro chemotaxis assays demonstrated that rMSMP increased monocyte migration (p< 0.001), and BETi treatment decreased migration of monocytes. Notably, treatment with the ABBV-075 selectively induced greater apoptosis in M2-like macrophages than in M1-like macrophages and ovarian cancer cells (p <0.01). M1-like macrophages (CD68+CD80+) were significantly increased after treatment with low dose ABBV-075 (p <0.05), while CD68+CCR2+ macrophages were significantly decreased. Furthermore, using RNA seq analysis, we found that ABBV-075 selectively downregulated chemokines, such as CCL2/CCR2, CCR1, and CCR5 in macrophages and matrix metalloproteinases (MMP19) and cyclin-dependent kinases (CDK15) in cancer cells. Finally, utilizing the SKOV3ip1 adaptive resistant ovarian cancer model, the combination of ABBV-075 and bevacizumab resulted in a 95% lower tumor weight compared to control (p<0.05). The combination also resulted in a 62.2% and 78.3% decrease in F4/80+ and ARG+ macrophages, respectively, compared to control (p<0.01). Conclusions: Our findings indicate a previously unrecognized role for BET inhibitors in selectively targeting CCR2+ macrophages and repolarizing the macrophages into M1-like phenotype. These findings may have implications for new combinations to overcome resistance to bevacizumab in ovarian cancer. Objectives: The diversity of tumor-associated macrophages (TAMs) is known to contribute to adaptive resistance to anti-VEGF therapy in ovarian cancer. CCR2+ macrophages are thought to have immunosuppressive effects and contribute to immune evasion through the CCL2-CCR2 axis. MSMP (a novel CCR2 ligand)/CCR2 axis plays an important role in promoting adaptive resistance in ovarian cancer models. Here, we examined the effects of BET inhibitors (BETis) (e.g., ABBV-075, CPI 203, and JQ1) on MSMP/CCR2 axis and CCR2+ TAMs in ovarian cancer resistant to anti-VEGF therapy. Methods: We used the TIMER and CIBERSORT analytical tools for estimating the associations between macrophages and CCR2 or clinical associations in ovarian cancer. We also carried out a series of in vitro (chemotaxis, apoptosis, flow cytometry, and RNA sequencing) and in vivo (adaptive resistant model of SKOV3ip1 ovarian cancer) experiments to determine the effects of BETis on the MSMP/CCR2 axis and overcoming resistance to bevacizumab in ovarian cancer. Results: CIBERSORT database revealed that high M1-like macrophages (tumoricidal) were associated with better overall survival of patients with ovarian cancer, while high M2-like macrophages (pro-tumoral) were associated with poor overall survival (p<0.01). TIMER analysis further revealed that CCR2 expression was significantly associated with monocyte and macrophage infiltration in ovarian cancer (p<0.01). To search druggable transcriptional factors of MSMP and CCR2, we used the transcriptomic database and western blot analyses and identified that BETi decreased MSMP expression in cancer cells and CCR2 in monocytes/macrophages, likely in a BRD4-dependent manner. In vitro chemotaxis assays demonstrated that rMSMP increased monocyte migration (p< 0.001), and BETi treatment decreased migration of monocytes. Notably, treatment with the ABBV-075 selectively induced greater apoptosis in M2-like macrophages than in M1-like macrophages and ovarian cancer cells (p <0.01). M1-like macrophages (CD68+CD80+) were significantly increased after treatment with low dose ABBV-075 (p <0.05), while CD68+CCR2+ macrophages were significantly decreased. Furthermore, using RNA seq analysis, we found that ABBV-075 selectively downregulated chemokines, such as CCL2/CCR2, CCR1, and CCR5 in macrophages and matrix metalloproteinases (MMP19) and cyclin-dependent kinases (CDK15) in cancer cells. Finally, utilizing the SKOV3ip1 adaptive resistant ovarian cancer model, the combination of ABBV-075 and bevacizumab resulted in a 95% lower tumor weight compared to control (p<0.05). The combination also resulted in a 62.2% and 78.3% decrease in F4/80+ and ARG+ macrophages, respectively, compared to control (p<0.01). Conclusions: Our findings indicate a previously unrecognized role for BET inhibitors in selectively targeting CCR2+ macrophages and repolarizing the macrophages into M1-like phenotype. These findings may have implications for new combinations to overcome resistance to bevacizumab in ovarian cancer.