Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8⁺ T Cells

Abstract Natural killer (NK) cells not only are innate effector lymphocytes that directly participate in tumor surveillance but are also essential helpers in the antitumor CD8⁺ T‐cell response. However, the molecular mechanisms and potential checkpoints regulating NK cell helper functions remain elusive. Here, it is shown that the T‐bet/Eomes‐IFN‐γ axis in NK cells is essential for CD8⁺ T cell‐dependent tumor control, whereas T‐bet‐dependent NK cell effector functions are required for an optimal response to anti‐PD‐L1 immunotherapy. Importantly, NK cell‐expressed TIPE2 (tumor necrosis factor‐alpha‐induced protein‐8 like‐2) represents a checkpoint molecule for NK cell helper function, since Tipe2 deletion in NK cells not only enhances NK‐intrinsic antitumor activity but also indirectly improves the antitumor CD8⁺ T cell response by promoting T‐bet/Eomes‐dependent NK cell effector functions. These studies thus reveal TIPE2 as a checkpoint for NK cell helper function, whose targeting might boost the antitumor T cell response in addition to T cell‐based immunotherapy.