Tumor-specific cytotoxic T cells unleashed by the blockade of immune checkpoints have to overcome a hostile tumor microenvironment (TME). They start from very small numbers of T cells with tumor antigen specificity and, despite expansion, likely remain at a numerical disadvantage to the tumor cells they target. To overcome these obstacles, we propose that T cells need to change the TME to make it permissive for their antitumor effects by altering the phenotype of cells beyond the cancer cells they are in physical contact with. In this process, IFNγ secreted by tumor-specific T cells plays a critical role, as it changes the expression of hundreds of genes in cancer cells and other immune cells in the TME up to 40 layers of cells away from their location, effectively turning these cells into enablers of the antitumor immune response. In this perspective, we postulate that the clinical activity of cancer immunotherapy with immune-checkpoint blocking antibodies and adoptively transferred T cells requires that cancer cells facilitate the antitumor immune response. IFNγ effectively changes the balance of power in the TME to enable the antitumor activity of tumor antigen-specific cytotoxic T cells.
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