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We introduce IN-situ DEtailed Phenotyping To High-resolution transcriptomics (IN-DEPTH), a streamlined, resource-efficient, commercially compatible workflow using single-cell spatial proteomics-derived imaging to guide transcriptomic capture on the same slide without RNA signal loss. To integrate modalities beyond niche-level mapping, we developed Spectral Graph Cross-Correlation (SGCC), a proteomic\u2013transcriptomic framework resolving spatially coordinated functional state changes across interacting cell populations. Applied to diffuse large B-cell lymphoma (DLBCL), IN-DEPTH and SGCC enabled stepwise discovery from Epstein\u2013Barr virus (EBV)\u2013positive and EBV-negative tumor comparisons with single-cell resolution, revealing coordinated tumor\u2013macrophage\u2013CD4 T-cell remodeling, immunosuppressive C1Q macrophage enrichment, CD4 T-cell dysfunction, and a candidate IL27\u2013STAT3 signaling axis. Collectively, IN-DEPTH enables scalable spatial multiomics to uncover clinically relevant microenvironmental mechanisms and toward robust spatial multimodal AI models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>IN-DEPTH enables same-slide spatial multiomics across commercial platforms via a protein-first strategy preserving protein epitopes, RNA quality, and tissue integrity. Coupled with SGCC, it resolves coordinated spatial immune remodeling, revealing EBV\/LMP1-driven C1Q macrophage polarization and CD4 T-cell dysfunction in DLBCL, with broad applicability to other diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0775","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T15:26:02Z","timestamp":1774365962000},"page":"1611-1648","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Same-Slide Spatial Multiomics Integration with IN-DEPTH Reveals Tumor Virus\u2013Linked Spatial Reorganization of the Tumor Microenvironment"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1792-247X","authenticated-orcid":false,"given":"Stephanie Pei Tung","family":"Yiu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04drvxt59","id-type":"ROR","asserted-by":"publisher"}],"name":"Beth 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