Mediator complex subunit 1 architects a tumorigenic Treg cell program independent of inflammation

While immunotherapy has revolutionized cancer treatment, its safety has been hampered by immunotherapy-related adverse events. Unexpectedly, we show that Mediator complex subunit 1 (MED1) is required for T regulatory (T_reg) cell function specifically in the tumor microenvironment. T_reg cell-specific MED1 deletion does not predispose mice to autoimmunity or excessive inflammation. In contrast, MED1 is required for T_reg cell promotion of tumor growth because MED1 is required for the terminal differentiation of effector T_reg cells in the tumor. Suppression of these terminally differentiated T_reg cells is sufficient for eliciting antitumor immunity. Both human and murine T_reg cells experience divergent paths of differentiation in tumors and matched tissues with non-malignant inflammation. Collectively, we identify a pathway promoting the differentiation of a T_reg cell effector subset specific to tumors and demonstrate that suppression of a subset of T_reg cells is sufficient for promoting antitumor immunity in the absence of autoimmune consequences.