Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-β pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-β in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-β resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates. Strikingly, co-silencing of TGF-β and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-β silencing also restored tumor sensitivity to tumor-specific cell therapies and markedly improved the efficacy of anti-PD-1/anti-CTLA-4 treatment. Thus, TGF-β and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.