CellLENS enables cross-domain information fusion for enhanced cell population delineation in single-cell spatial omics data.

Delineating cell populations is crucial for understanding immune function in health and disease. Spatial omics technologies offer insights by capturing three complementary domains: single-cell molecular biomarker expression, cellular spatial relationships and tissue architecture. However, current computational methods often fail to fully integrate these multidimensional data, particularly for immune cell populations and intrinsic functional states. We introduce Cell Local Environment and Neighborhood Scan (CellLENS), a self-supervised computational method that learns cellular representations by fusing information across three spatial omics domains (expression, neighborhood and image). CellLENS markedly enhances de novo discovery of biologically relevant immune cell populations at fine granularity by integrating individual cells' molecular profiles with their neighborhood context and tissue localization. By applying CellLENS to diverse spatial proteomic and transcriptomic datasets across multiple tissue types and disease settings, we uncover unique immune cell populations functionally stratified according to their spatial contexts. Our work demonstrates the power of multi-domain data integration in spatial omics to reveal insights into immune cell heterogeneity and tissue-specific functions.