Same-Slide Spatial Multiomics Integration with IN-DEPTH Reveals Tumor Virus–Linked Spatial Reorganization of the Tumor Microenvironment
Year: 2026
Type: article
Abstract: Spatial transcriptomics and proteomics have enabled profound insights into tissue organization, yet these technologies remain largely disparate, and emerging same-slide multiomics approaches are limited in plex, spatial resolution, signal retention, and integrative analytics. 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-transcriptomic 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-Barr virus (EBV)-positive and EBV-negative tumor comparisons with single-cell resolution, revealing coordinated tumor-macrophage-CD4 T-cell remodeling, immunosuppressive C1Q macrophage enrichment, CD4 T-cell dysfunction, and a candidate IL27-STAT3 signaling axis. Collectively, IN-DEPTH enables scalable spatial multiomics to uncover clinically relevant microenvironmental mechanisms and toward robust spatial multimodal AI models. SIGNIFICANCE: 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.
Source: Cancer Discovery
Authors: Stephanie Pei Tung Yiu, Yuzhou Chang, Yao Yu Yeo, Huaying Qiu, Wenrui Wu, Hendrik A. Michel, Xiaojie Jin, Rongting Huang, Shoko Kure, Lindsay Parmelee, Shuli Luo, Precious Cramer, Jia Le Lee, Yang Wang, Zhangxin Zhao, Jason Yeung, Nourhan El Ahmar, Berkay Simsek, Razan Mohanna, McKayla Van Orden, Wesley S. Lu, Kenneth J. Livak, Shuqiang Li, Ce Gao, Melinda Burgess, Colm Keane, Jahanbanoo Shahryari, Leandra G. Kingsley, Reem N. Al-Humadi, Sahar Nasr, Dingani Nkosi, Sam Sadigh, Philip Rock, Leonie Frauenfeld, Louisa Kaufmann, Bokai Zhu, Ankit Basak, Nagendra Dhanikonda, Chi Ngai Chan, Jordan Krull, Ye Won Cho, Chia-Yu Chen, Jonathan Brown, Hongbo Wang, Bo Zhao, Jia-Ying Joey Lee, Lit-Hsin Loo, David M. Kim, Vassiliki A. Boussiotis, Baochun Zhang, Kevin Wei, Alex K. Shalek, Brooke E. Howitt, Sabina Signoretti, Christian M. Schürch, F. Stephen Hodi, W. Richard Burack, Scott J. Rodig, Qin Ma, Sizun Jiang
Institutions: Beth Israel Deaconess Medical Center, Harvard University, Pelotonia, The Ohio State University, Stanford University, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Brigham and Women's Hospital, Translational Research Institute, The University of Queensland, University of Rochester Medicine, University of Tübingen, Broad Institute, Massachusetts Institute of Technology, University of Dayton, Agency for Science, Technology and Research, Bioinformatics Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: Cancer Research Institute, Bristol-Myers Squibb, AstraZeneca, Sanofi, Gilead Sciences, Dana-Farber/Harvard Cancer Center, Life Sciences Research Foundation, Exelixis, Pelotonia, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Paul G. Allen Frontiers Group, National Institutes of Health, Genentech, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke
Awards: The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity, Statistical Power Analysis Framework for Multi-Sample and Cross-Platform Spatial Omics Experiments, G9000071433, G9000116651, G9000227279, G9000235671, G9000263970, G9000316125, Dissecting Orchestrated Immune Responses to Glioblastoma within the Native Tissue Microenvironment to Improve Treatment Outcomes, Single cell investigation of co-evolution in cancer cells and host cell immune microenvironment, Navigating Pathways of Innate Immunity and Epigenetic Memory in Checkpoint Immunotherapy, DF/HCC Prostate SPORE, Spatial-Temporal Dissection of Stratified Host Tissue Responses to Severe acute respiratory syndrome-related coronaviruses in situ to Understand Intra-host Pathogenesis
OpenAlex ID: W7140177999