Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors

Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments. [Display omitted] •Spatial -omic atlas of CRC reveals regional heterogeneity across progression states•Regional mutations and copy number changes anchor evolutionary reconstruction•Progression along the CIN+ trajectory drives suppression of cytotoxic immunity•Accompanying epithelial gene signature predicts immune exclusion and poor outcomes A spatial multi-omic atlas uncovers the diverse genetic and transcriptomic landscape of human colorectal lesions along progression to malignancy, highlighting the relationship between CRC evolution and tumor cytotoxic immunity. The identified immune exclusion (IEX) signature emerges as a predictor of poor patient outcomes, serving as potential biomarkers for prognosis and targeted treatment.