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However, cross\u2010integration of structurally unpaired and underutilized morphomic datasets (e.g., Hematoxylin and eosin (H&amp;E)\u2010stained images), remains a bottleneck due to inherent differences in spot structures, feature dimensions, and cellular heterogeneities. Here, we present AgaeSMO, an adaptive graph auto\u2010encoder for versatile cross\u2010modality integration of both structurally paired and unpaired spatial multi\u2010omics data. AgaeSMO encodes each omics modality from a cell type\u2010aware KNN (k\u2010nearest neighbor)\u00a0feature graph and a spatial adjacency graph, while leverages GATs (Graph Attention Networks) as the backbone to fuse modalities by learning joint representations through an attention\u2010weighted module. It specially fuses structurally unpaired modalities, which applies a morphological transformation strategy by designing a cross\u2010guidance alignment among modalities through graph cross\u2010attention learning. H&amp;E images are treated as a standalone morphomic modality (rather than auxiliary features) is specially fused with other modalities through image patch embeddings to fully utilize cellular morphological heterogeneities. AgaeSMO is a powerful tool can effectively integrate diverse omics modalities with both paired and unpaired spot architectures. These unique capabilities enable precise spatial domain delineation, micro\u2010environmental heterogeneity detection, compatible across broad platforms, that outperforming pre\u2010existing tools. AgaeSMO offers a versatile, robust framework for integrative spatial multi\u2010omics analysis and facilitates multimodal, biologically interpretable mining.<\/jats:p>","DOI":"10.1002\/advs.78141","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:19:42Z","timestamp":1791865182000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Flexible Integration of Structurally Diverse Spatial Multi\u2010Omics With AgaeSMO"],"prefix":"10.1002","author":[{"given":"Kunpeng","family":"Liu","sequence":"first","affiliation":[{"name":"Center for Genomics and Biotechnology Fujian Provincial Key Laboratory of Haixia Plant Systems Biology Haixia Institute of Science and Technology College of Life Sciences Fujian Agriculture and Forestry University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinpo","family":"Su","sequence":"additional","affiliation":[{"name":"Center for Genomics and Biotechnology Fujian Provincial Key Laboratory of Haixia Plant Systems Biology Haixia Institute of Science and Technology College of Life Sciences Fujian Agriculture and Forestry University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Genomics and Biotechnology Fujian Provincial Key Laboratory of Haixia Plant Systems Biology Haixia Institute of Science and Technology College of Life Sciences Fujian Agriculture and Forestry University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Shen","sequence":"additional","affiliation":[{"name":"Center for Genomics and Biotechnology Fujian Provincial Key Laboratory of Haixia Plant Systems Biology Haixia Institute of Science 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Biotechnology Fujian Provincial Key Laboratory of Haixia Plant Systems Biology Haixia Institute of Science and Technology College of Life Sciences Fujian Agriculture and Forestry University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenglin","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Genomics and Biotechnology Fujian Provincial Key Laboratory of Haixia Plant Systems Biology Haixia Institute of Science and Technology College of Life Sciences Fujian Agriculture and Forestry University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Genomics and Biotechnology Fujian Provincial Key Laboratory of Haixia Plant Systems Biology Haixia Institute of Science and Technology College of Life Sciences Fujian Agriculture and Forestry University  Fuzhou 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