Mapping the Microenvironment: How Spatial‐Omics Is Advancing the Understanding of Allograft Fate

Solid organ transplantation is a life-saving procedure, yet its long-term success is limited by rejection and other pathological processes. Traditional histopathology and bulk molecular analysis lack the necessary spatial resolution to resolve the complex cellular interactions within the allograft microenvironment. The emergence of spatial-omics technologies offers new capabilities for molecular analysis within intact tissue architecture. This review provides an overview of major spatial transcriptomic and proteomic platforms, including sequencing-based technologies, imaging-based technologies, and high-plex protein imaging technologies. We synthesize and provide mechanistic insights into the key findings from the application of these tools in kidney, lung, liver, and heart transplantation. Key applications discussed include as follows: resolving the heterogeneity of rejection (T-cell mediated and antibody-mediated rejection (ABMR)), elucidating the driving mechanisms of chronic allograft dysfunction and ischemia-reperfusion injury (IRI), and delineating the immune microenvironments associated with operational tolerance (OT) and tertiary lymphoid structures (TLS). We further explore how these technologies are beginning to refine our understanding of transplant pathology from a diffuse inflammatory process to the identification of specific pathogenic microenvironments. Finally, we discuss the challenges and prospects of translating these powerful research tools toward the long-term goal of precision immunosuppression, for instance, through the potential future development of digital biopsies to help guide individualized therapies.