Multi-modal Graph Integration for Biologically Interpretable Domain Identification Using Spatial Transcriptomics

Functional domain identification in spatial transciptomics transforms spatial molecular measurements into mechanistic insights into tissue physiology and pathology. However, the inherent noise and sparsity of gene expression data, along with the locality-biased design of conventional graph-based approaches, fundamentally limit the accurate identification of complex tissue domains. In this study, we propose a novel Biologically Interpretable multi-modal Graph using Spatial Transcriptomics, called BIGraph-ST, that integrates pathway activity scores and histological image features for robust spatial domain identification. BIGraph-ST represents modality-specific similarity through affinity graphs and propagates spatial topology to capture higher-order connectivity within the tissue microenvironment. Experimental results demonstrated robust performance and notable improvements across multiple gold-standard benchmark datasets, particularly in cancer tissues. Moreover, BIGraph-ST provides biologically interpretable pathway-level representations of domains, which ultimately offers a valuable tool to gain biological in-sights into complex tissue architectures. The source code will be publicly available upon acceptance.