Current anticancer therapy is a delicate balance between elimination of malignant cells and harmful sideeffects for the host. In this study, we used a tumor-homing peptide to engineer anti-CD40 agonist antibodiesand recombinant IL-2 such that they were selectively delivered into spontaneously arising tumors in atransgenic mouse model of islet cell carcinogenesis. Intravenous injection of these agents, either separatelyor together, led to accumulation in the vicinity of tumor neovessels without toxic side effects. Although bothmolecules are critical for adaptive immunity, the most profound effects were seen in endothelial cells. Combined,local anti-CD40 and IL-2 therapy reduced tumor vascularity and significantly delayed tumor growthin mice. Remarkably, tumor-bearing mice remained disease-free long-term when targeted anti-CD40 and IL-2were combined with transfers of preactivated antitumor immune cells. In this therapeutic setting, triggeringof CD40 on endothelial cells induced an inflammatory response of the vessel wall and facilitated effector cellaccumulation in the tumor parenchyma while IL-2 promoted antigen-specific immune cell persistence. Webelieve this is a novel and highly effective anticancer approach, whereby tumor stroma is “conditioned” forenhanced immune cell entry and survival, facilitating immune-mediated tumor destruction and leading to asustained antitumor response.