HEDeST: An Integrative Approach to Enhance Spatial Transcriptomic Deconvolution with Histology

Abstract Spatial organization of cells is essential for tissue function, yet sequencing-based spatial transcriptomics often lacks single-cell resolution. We present HEDeST, a weakly supervised framework that integrates histology-derived morphological features with deconvolution-derived spot-level proportions to assign cell types at single-cell resolution. HEDeST is robust to technical variability, adaptable to user-defined cell types, and compatible with any deconvolution method. Across simulated and semi-simulated datasets, HEDeST outperforms existing morphology-based approaches and reveals biologically meaningful microenvironments when applied to real cancer datasets, providing a scalable tool for high-resolution spatial tissue analysis.