Intratumoral T_reg cell ablation elicits NK cell-mediated control of CD8 T cell-resistant tumors

Cancer cells frequently lose major histocompatibility complex class I (MHC I) to evade CD8 T cell recognition. Natural killer (NK) cells are poised to target MHC I-deficient cancer cells, but MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here, we show that selective intratumoral (IT) ablation of regulatory T cells (T_reg cells) elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I⁺ cancers that expressed NKG2D ligands. T_reg cells controlled the activation, maturation, and antitumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, depletion of IT-T_reg cells relieved the inhibition of cDC2-dependent induction of IL-2 production by conventional CD4 T cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT-T_reg cells similarly empowered NK cell-dependent tumor control. These findings expand the breadth of T_reg cell-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that therapeutic targeting of T_reg cells in tumors can control CD8 T cell-resistant cancers.