Spatial instruction of tissue immunity.

Tissue immunity must meet the architectural and physiological demands of each organ, from viral entry in the respiratory tract to immune surveillance in the gastrointestinal mucosa. Recent advances in spatial technologies and computational biology now allow us to map entire immune communities in situ, capturing not only their composition but their positional logic, connectivity patterns, and local transcriptional landscapes. These tools are revealing that immune function is not evenly distributed but is patterned along regionalized cytokine gradients, anatomical landmarks, and physical niches that confer specialized capabilities. Understanding the principles driving this spatiotemporal logic is essential to decipher how immune networks are built, maintained, and subverted in disease. To this end, network topology analyses, immune allocation plots, and spatial reference frameworks are beginning to define the "wiring diagrams" of immunity, while emerging perturbation-coupled spatial approaches enable causal dissection of the signals that program location-specific phenotypes. These insights have broad implications, from explaining why certain organs resist tumor initiation or metastasis, to revealing metabolic constraints on immune cells in solid tumors, to understanding clonal lymphocyte dynamics in health and disease. Here, we synthesize recent conceptual and technological advances that are transforming how we study tissue immunity; highlight exemplar findings from infection, cancer, and autoimmunity; and outline the experimental and computational innovations needed to bridge key knowledge gaps. We propose that the next phase of immunology will require integrating multiomic, high-resolution spatial data with predictive models of immune behavior to forecast disease risk, design personalized therapies, and ultimately deploy immune protection at the right place and time.