Marco De Giovanni, Donato Inverso, Matteo Iannacone
The immune system is deeply shaped by its anatomical context, with spatial organization emerging as a fundamental principle of immune regulation. Recent advances in spatial omics technologies-encompassing transcriptomics, proteomics, metabolomics, lipidomics, and phosphoproteomics-have revolutionized our ability to study immune processes within intact tissue environments. By preserving spatial coordinates while capturing high-dimensional molecular data, these technologies offer unprecedented insight into how immune cell states and functions are governed by local cues and tissue architecture. In this review, we provide an overview of the major spatial omics platforms, emphasizing methodologies that have gained traction within the immunology community and in our own research. We then illustrate how these tools have begun to elucidate the logic of immune compartmentalization across anatomically complex tissues. While not exhaustive, we highlight selected examples from the intestine, secondary lymphoid organs, and liver to show how spatial omics has uncovered region-specific immune programs, microenvironmental niches, and context-dependent signaling pathways. Together, these studies demonstrate how spatial omics technologies are redefining immunological inquiry-shifting the focus from isolated cell types to their spatially embedded roles in tissue physiology and pathology.