EnrichMap: Spatially informed enrichment analysis for functional interpretation of spatial transcriptomics

Advances in spatial transcriptomics (ST) allow high-resolution mapping of gene expression within intact tissues, revealing spatially regulated biology. However, accurately quantifying gene set activity in spatial contexts remains inadequate. We present EnrichMap, a Python package designed to compute gene set enrichment scores in ST data by integrating batch correction, smoothing and spatial confounder adjustment. EnrichMap generates enrichment scores for signatures or pathways, with an optional framework for incorporating gene weights. To assess performance, we benchmark EnrichMap against established scoring techniques using spatial autocorrelation metrics such as Morans I. Our results show that EnrichMap improves spatial coherence, producing scores that capture both local and global spatial patterns, while conventional approaches tend to exhibit higher heterogeneity or diminished spatial structure. EnrichMap is demonstrated to be generalisable across a variety of ST platforms, including Visium, Xenium, MERFISH and imaging mass cytometry, maintaining consistent performance despite differences in spatial resolution and detection chemistry. Our method offers a platform-agnostic, spatially and biologically meaningful representation of gene set activity across complex tissue landscapes.