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Accurately capturing this structural complexity and decoding the underlying biological processes requires effectively integrating data from multiple modalities. However, transitioning to subcellular resolutions introduces massive data scales and severe transcriptomic sparsity, which challenge current analytical frameworks. To address this, we present HESTIA (Histology-Enhanced Scalable cross-Resolution inTegration for spatial trAnscriptomics), a highly efficient multimodal algorithm designed for identifying spatial domains in large-scale, high-resolution spatial omics data. By circumventing memory-intensive computations, HESTIA efficiently processes massive datasets on which existing algorithms fail due to memory constraints. HESTIA outperforms current multimodal methods in clustering accuracy and spatial continuity, accurately delineating fine structural boundaries. Furthermore, applying HESTIA to large-scale pathological samples successfully dissects clinically relevant intratumoral heterogeneity and maps distinct immune microenvironments in lung and colorectal cancers.<\/jats:p>","DOI":"10.1093\/bib\/bbag512","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:37:44Z","timestamp":1788521864000},"source":"Crossref","is-referenced-by-count":0,"title":["HESTIA: scalable multimodal integration of histology and high-resolution spatial Transcriptomics for robust spatial domain identification"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1262-4115","authenticated-orcid":false,"given":"Zheng","family":"Zhong","sequence":"first","affiliation":[{"name":"BGI Research, BGI Center , No. 9 Yunhua Road, Yantian District, Shenzhen, 518083 ,","place":["China"]},{"name":"STOmics Tech Co., Ltd., BGI Center , No. 9 Yunhua Road, Yantian District, Shenzhen 518083 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