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While single\u2010cell technologies have advanced our understanding of this process, spatial dynamics remain incompletely characterized. Here, whole\u2010exome sequencing (WES), imaging mass cytometry (IMC), and spatial transcriptomics (ST) were integrated to study molecular evolution and immune responses in two lung adenocarcinoma (LUAD) mouse models: a genetically engineered model (129S4\/Sv\u2010Kras\n                    <jats:sup>LSL\u2010G12D<\/jats:sup>\n                    , termed 129S4 K) and a carcinogen\u2010induced precancer model (129S4 U). Compared to 129S4 K, 129S4 U tumors exhibited higher mutational, neoantigen but lower copy number variation (CNV) burdens at matched developmental timepoints, consistent with findings of higher mutational burden in human smoking\u2010related LUAD than nonsmoking LUAD. We profiled over 1.4 million spatial single cells from 284 IMC regions of interest and 51,531 spatial transcriptomic spots from 156 lesions across 141 mice. Macrophage abundance increased with tumor progression, while CD8 T\u2010cell and B\u2010cell densities declined in late\u2010stage LUAD. 129S4 U showed greater immune infiltration in both tumor and adjacent normal tissue, higher T\u2010cell cytotoxicity signature score in line with its higher mutational and neoantigen burdens. LUAD progression was marked by early morphological shifts and late\u2010stage changes in cell states and interactions. These data define spatial and genetic landscapes of LUAD development and provide a framework for investigating immune evolution and therapeutic strategies in early carcinogenesis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512597","type":"journal-article","created":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T08:50:07Z","timestamp":1769331007000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Spatial Profiling Reveals Distinct Molecular and Immune Evolution of Mouse Lung Adenocarcinoma Precancers with or Without Carcinogen Exposure"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2439-0026","authenticated-orcid":false,"given":"Bo","family":"Zhu","sequence":"first","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"Genomic Medicine The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Aminu","sequence":"additional","affiliation":[{"name":"Imaging Physics The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute for Data Science in Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"Translational Molecular Pathology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Rong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanpeng","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Genetics Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Li","sequence":"additional","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"Genomic Medicine The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Tian","sequence":"additional","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"Genomic Medicine The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao\u2010Wei","family":"Lu","sequence":"additional","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"},{"name":"Genomic Medicine The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Medicine Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Hu","sequence":"additional","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ye","sequence":"additional","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew Y.","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of Thoracic\/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cancer Systems Imaging The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank R.","family":"Rojas","sequence":"additional","affiliation":[{"name":"Translational Molecular Pathology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parra Cuentas. 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