Intra-Tumoral Treg Ablation Unleashes NK Cell-Mediated Control of CD8 T Cell-Resistant Tumors

Abstract Cancer cells frequently lose MHC I to evade CD8 + T cell recognition. While Natural Killer (NK) cells are poised to target MHC I-deficient cancer cells, MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here we show that selective intra-tumoral (IT) ablation of regulatory T (Treg) cells elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I + cancers. Tregs controlled the activation, maturation, and anti-tumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, IT Tregs prevented the cDC2-dependent induction of IL-2 production by CD4 + Tconv cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT Tregs similarly empowered NK- dependent tumor control. These findings expand the breadth of Treg-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that targeting Tregs in tumors can control CD8 + T cell-resistant cancers. One Sentence Summary IT Treg ablation drives NK cell tumor control via CD4 + Tconv-derived IL-2, eliminating MHC I+/MHC I- cancers without systemic toxicity.