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Aiming to improve the accuracy and completeness of intercellular gene-regulatory network inference, we constructed a novel spatial-resolved gene-regulatory network framework (spGRN). Methods: Firstly, the spatial multi-omics data of colorectal cancer (CRC) patients were analyzed. We precisely located the tumor boundaries and then systematically constructed the spGRN framework to study the network regulation. Subsequently, the key signaling molecules obtained by the spGRN were identified and further validated by the spatial-proteomics dataset. Results: Through the constructed spatial gene regulatory network, we found that in the communication with malignant cells, the highly expressed ligands LIF and LGALS3BP and receptors IL6ST and ITGB1 in fibroblasts can promote tumor proliferation, and the highly expressed ligands S100A8\/S100A9 in plasma cells play an important role in regulating inflammatory responses. Further, validation of the key signaling molecules by the spatial-proteomics dataset highlighted the role of these genes in mediating the regulation of boundary-related cells. Furthermore, we applied the spGRN to publicly available single-cell and spatial-transcriptomics datasets from three other cancer types. The results demonstrate that ITGB1 and its target genes FOS\/JUN were commonly expressed in all four cancer types, indicating their potential as pan-cancer therapeutic targets. Conclusion: the spGRN was proven to be a useful tool to select signal molecules as potential biomarkers or valuable therapeutic targets.<\/jats:p>","DOI":"10.3390\/genes16070821","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T10:46:05Z","timestamp":1752662765000},"page":"821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Construction of Gene Regulatory Networks Based on Spatial Multi-Omics Data and Application in Tumor-Boundary Analysis"],"prefix":"10.3390","volume":"16","author":[{"given":"Yiwen","family":"Du","sequence":"first","affiliation":[{"name":"College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, The Department of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, The Department of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, The Department of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4393-6250","authenticated-orcid":false,"given":"Lanming","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation (Shanghai), China Ministry of Agriculture, College of Food Science, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4465-5925","authenticated-orcid":false,"given":"Zhenhao","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, The Department of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Xie","sequence":"additional","affiliation":[{"name":"College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"Shanghai-MOST Key Laboratory of Health and Disease Genomics, The Department of Genome and Bioinformatics, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai 200237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-020-00292-x","article-title":"Deciphering cell-cell interactions and communication from gene expression","volume":"22","author":"Armingol","year":"2021","journal-title":"Nat. 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