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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\u2010omics 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\u2010based technologies, imaging\u2010based technologies, and high\u2010plex 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\u2010cell mediated and antibody\u2010mediated rejection (ABMR)), elucidating the driving mechanisms of chronic allograft dysfunction and ischemia\u2010reperfusion 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\u2010term goal of precision immunosuppression, for instance, through the potential future development of digital biopsies to help guide individualized therapies.<\/jats:p>","DOI":"10.1111\/ctr.70373","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T02:46:32Z","timestamp":1764729992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mapping the Microenvironment: How Spatial\u2010Omics Is Advancing the Understanding of Allograft Fate"],"prefix":"10.1111","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6232-8341","authenticated-orcid":false,"given":"Lisha","family":"Mou","sequence":"first","affiliation":[{"name":"Shenzhen Xenotransplantation Medical Engineering Research and Development Center Institute of Translational Medicine Shenzhen Second People's Hospital  Shenzhen China"},{"name":"MetaLife Lab Shenzhen Institute of Translational Medicine  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuhui","family":"Pu","sequence":"additional","affiliation":[{"name":"MetaLife Lab Shenzhen Institute of Translational Medicine  Shenzhen China"},{"name":"Imaging Department  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001377\u20109"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2021.11.029"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006594\u20104"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajt.2023.10.031"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2021.11.028"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1554876"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20209682"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931\u2010024\u201002682\u20109"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2021.03.007"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpha.2023.07.002"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.161078"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004150\u20102"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943\u2010023\u201001876\u2010x"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010025\u201001475\u2010z"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2022.02.023"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538\u20107445.AM2024\u20101159"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000004466"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12162042"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010024\u201001596\u20109"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010022\u201001448\u20102"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0000000000004587"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1159\/000538344"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl\u20102019\u2010319866"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adm6783"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26093949"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43556\u2010023\u201000144\u20100"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010022\u201001517\u20106"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010025\u201003543\u20104"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1581"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13060522"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.890410"},{"key":"e_1_2_12_33_1","unstructured":"\u201cSpatial Multiomics Enabled with GeoMx DSP. 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