Abstract Recent studies described a resistance to the anti-angiogenic therapy both in pre-clinical and clinical settings. Several mechanisms that contribute to this resistance has been so far proposed and, among these, the recruitment of bone marrow-derived cells to the tumors, seems to be critical. We have previously showed that an amino-bisphosphonate, Zoledronic acid (ZA), in a mouse model of spontaneous cervical carcinogenesis (HPV16/E2) by targeting MMP-9+ tumor-associated macrophages (TAM), strongly inhibited cancer progression and angiogenesis. Stemming from these data we sought to investigate whether ZA by acting on TAM, was able to overcome the resistance to anti-angiogenic treatments. We treated tumor-bearing HPV16/E2 mice with ZA alone or combined with the small molecule tyrosine kinase inhibitor Sunitinib or with an anti-VEGFR-2 antibody, DC101, to assess the ability of ZA to block metastasis dissemination. Notably ZA synergized with Sunitinib and DC101 to inhibit primary tumor growth. Interestingly, while these compounds increased the incidence and the number of liver and lung metastasis, ZA alone inhibited basal tumor metastasis in parallel to angiogenesis inhibition. ZA combined with Sunitinib or DC101 showed a greater effect in impairing liver and lung metastasis formation. Confocal analysis of the vasculature revealed that while Sunitinib- or DC101-treated cancers displayed poorly functional vessels, both ZA alone or combined with Sunitinib or DC101 efficiently induced a normalized vasculature highly covered by pericytes and better perfused. Remarkably, gene and protein expression analysis of FACS-sorted macrophages derived from tumors of the different treatment groups, showed that ZA alone or combined with Sunitinib or DC101 inhibited the expression of M2-markers such as MRC-1, Il-10, CCL22 and MMP-9 and simultaneously enhanced the levels of M1-markers such as Il12 and CXCL9 in these cells. We conclude that ZA, by promoting a M1-like macrophages phenotype in HPV16/E2 cervical cancers and consequently inducing a normalized vasculature, efficiently overcomes the resistance to angiogenesis inhibition by blocking metastasis dissemination. Citation Format: Stefania Capano, Federica Maione, Oriol Casanovas, Federico Bussolino, Enrico Giraudo. Zoledronic acid overcomes the resistance to the anti-angiogenic therapy and normalizes tumor vessels by switching from a M2- to a M1-like macrophages phenotype in a mouse model of spontaneous cervical cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4807. doi:10.1158/1538-7445.AM2014-4807