The stroma of solid tumors is a complex network of different cell types. We analyzed stroma cell interactions in two tumor models during cyclophosphamide (Cy)-induced tumor rejection. In growing tumors, tumor infiltrating macrophages (TIMs) produced interleukin (IL)-10. Beginning 6 h after Cy-treatment T cells in the tumor were inactivated and TIMs switched to interferon (IFN)-γ production. Both, IL-10 production before and IFN-γ production after Cy-treatment by TIMs required T cells. With the same kinetics as TIMs started to produce IFN-γ the tumor vasculature was destroyed which required IFN-γ receptor expression on host but not tumor cells. These events preceded hemorrhagic necrosis and residual tumor cell elimination by T cells. Together, T cells regulate the function of TIMs and tumor rejection can be induced by disturbing the stroma network.