Spatially instructed checkpoints in antitumor NK cell immunity.

Natural killer (NK) cell immunotherapies remain less effective in solid tumors than in hematologic malignancies. Poor infiltration, checkpoint engagement, and metabolic stress contribute, but these mechanisms often operate within spatially organized niches. We develop the concept of spatially instructed checkpoints: inhibitory programs locally induced or maintained whose functional impact depends on position. We organize evidence across tissue-level exclusion, suppressive cellular neighborhoods, and the cytotoxic synapse, distinguishing causal findings from associations and hypotheses. Spatial organization is an integrating layer that interacts with, rather than replaces, intrinsic, soluble, metabolic, transcriptional, and epigenetic mechanisms. We propose a translational framework for converting spatial discoveries into deployable assays that identify the dominant barrier and guide mechanism-matched strategies to restore antitumor NK cell activity.