Geometry-aware ligand-receptor analysis distinguishes interface association from spatial localization and reveals a continuum of tumor communication

Abstract

Spatial transcriptomics enables inference of cell-cell communication through ligand-receptor (LR) interactions, but current prioritization strategies often rely on expression strength or interface-associated enrichment without explicitly modeling tissue geometry. As a result, interactions associated with population interfaces are frequently interpreted as spatially localized even when their underlying expression is broadly distributed. Here, we present a geometry-aware framework for LR prioritization that explicitly separates interface structure from spatial localization within a locked and reproducible analysis pipeline. We quantify interface-associated communication using a distance-weighted boundary score defined on a spatial neighbor graph, evaluate interface specificity using a label-permutation null model that preserves spatial geometry, and compute an LR-specific localization score that captures the proximity of ligand and receptor expression to the corresponding interface. This framework distinguishes interface-associated compatibility from interaction-level spatial concentration. Across spatial transcriptomics datasets from breast cancer, colorectal cancer, melanoma, and pancreatic ductal adenocarcinoma, interface-aware ranking consistently recovers pathway families associated with extracellular matrix, adhesion, inflammatory, and immune-related processes. However, interface enrichment frequently shows limited separation from the null model, indicating that interface structure alone does not establish spatial specificity. Incorporating geometric localization substantially alters LR prioritization, distinguishing interactions that are concentrated near interfaces from those that are more diffusely distributed. Under a fixed, deterministic pipeline applied identically across datasets without parameter tuning, discrete spatial communication regimes were not reproducibly recovered. Instead, variation across samples is more consistently captured as continuous differences in geometry-aware attenuation, reflecting the degree to which inferred interactions are spatially constrained by tissue architecture. Together, these results demonstrate that interface-associated enrichment and spatial localization are distinct properties of inferred LR interactions, and that accurate interpretation of spatial communication requires explicit modeling of tissue geometry. Under this framework, tumor communication is more consistently described as a continuum of spatial constraint.