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Histology-Aware Graph for Modeling Intercellular Communication in Spatial Transcriptomics

Wang, X.; Tao, C.; Jiang, Y.; Liu, H.; Jiang, Z.; Zhu, P.; Que, N.; Xi, J.; Price, S.; Mou, Y.; Li, C.

2026-01-23 bioinformatics
10.64898/2026.01.22.701166 bioRxiv
Show abstract

Cell-cell communication (CCC) is essential to how life forms and functions. Recent tools achieve single-cell-resolved CCC inference utilizing spatial transcriptomics (ST). However, most ignore the modeling of tissue contexts surrounding cells, causing high false-positive/negative rates. Here, we propose HARMONIC, a CCC inference method integrating multimodal ST and hematoxylin and eosin (H&E)-stained images. HARMONIC causally modeling the transcriptomic-to-contextual relationships for CCC inference. The state-of-the-art performance was verified across ST platforms, species and healthy/diseased status, on both synthetic and biological samples. HARMONIC was applied in various real-world scenarios, especially on tissues with clear morphological boundaries, including cortical layers in mouse brain, medullary-cortex structures in mouse kidney, as well as tumor-stromal/immune interface. Significant refinement of false-positive/negative predictions was observed compared to ST-only CCC tools.

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