Abstract
Spatial omics technologies can help identify spatially organized biological processes, but existing computational approaches often overlook structural dependencies in the data. Here, we introduce Smoother, a unified framework that integrates positional information into non-spatial models via modular priors and losses. In simulated and real datasets, Smoother enables accurate data imputation, cell-type deconvolution, and dimensionality reduction with remarkable efficiency. In colorectal cancer, Smoother-guided deconvolution reveals plasma cell and fibroblast subtype localizations linked to tumor microenvironment restructuring. Additionally, joint modeling of spatial and single-cell human prostate data with Smoother allows for spatial mapping of reference populations with significantly reduced ambiguity.