Tissue-Specific Spatial Regulation of Innate Immune Checkpoints in Cancer

NK and innate lymphoid cells (ILC) regulate tissue homeostasis and immune responses by acting as early sensors of cellular stress and tissue dysfunction. Their functions are tightly controlled by regulatory circuits, often referred to as checkpoints, and are profoundly shaped by local environments. In cancer, tissue perturbations cause immune cell recruitment, spatial redistribution, and accordant functional adaptations. In this review, we discuss how tissue-specific cues regulate NK/ILC functions in cancer, and how local regulatory circuits shape their cellular states and effector programs. We address how targeting innate checkpoints could aid existing therapies and inform novel strategies for treating solid malignancies. SIGNIFICANCE: Recent progress in spatial and tissue-resolved immunology has highlighted the crucial influence of the tumor microenvironment and local cellular interactions on shaping immune cell compartmentalization and the tissue- and niche-driven specialization within the tumor tissue. This review redefines immune checkpoints not merely as static brakes on effector function, but as dynamic regulatory units that orchestrate immune cell adaptation to the evolving tumor milieu. We elucidate how NK cells and other innate lymphocytes undergo spatiotemporal adaptation across distinct tumor niches and provide an integrated understanding of innate checkpoint biology to unveil innovative therapeutic opportunities for modulating immune reactivity in solid malignancies.