Tumor immunotherapy has seen progress in recent years and celebrated successes with the FDA approval of Provenge and ipilimumab as immunotherapies for prostate cancer and melanoma, respectively. Although these therapies have focused on activating tumor-specific T cells, it has become increasingly clear in recent years that activating T cells in the periphery does not translate into clinical success, due, in large part, to the interactions of the immune system with the TME.The interplay between the immune system and tumor is clearly shown by the concept of immunoediting, where the immune system, by targeting developing tumors, selects for those variants that can escape and become malignant . Yet the question remains, are edited tumors really nonimmunogenic? The answer would seem to be “No” as simple therapies such as anti-CTLA-4 or anti-PD1 have shown dramatic reductions in tumor size in some clinical settings. One possible explanation for the somewhat surprising result is that in mouse models, tumors develop quickly, whereas in reality, tumors develop over the course of years, giving them the opportunity to develop both driver and passenger mutations that the immune system can recognize. Still not all tumors treated with single immunotherapeutic agents regress, showing that though important, activating T cells is not the only challenge to successful immunotherapy