Abstract
In humans, cell-cell communication orchestrates tissue organization, immune coordination, and repair, yet spatially mapping these interactions remains a challenge for biology. We introduce STARComm, a scalable-interpretable computational method that identifies Multicellular Communication Interaction Modules (MCIMs) by detecting spatially co-located receptor-ligand activity from high-plex spatial transcriptomics in 2D and 3D. Applied to an atlas of >14million cells across 8 cancers, STARComm revealed 24 conserved and tumor-specific MCIMs, including a fibro-immune module with targetable axes linked to immune exclusion and immunotherapy resistance. In chronic graft-versus-host disease, STARComm identified three salivary gland MCIMs predictive of patient death and two druggable axes ( CXCL12-CXCR4 , CCL5-SDC4 ), both with FDA-approved therapeutics. STARComm demonstrated that peripheral tissue profiling can forecast fatality nearly 3 years in advance using minor salivary glands. By enabling scalable biomarker discovery, drug targeting, and spatially resolved precision profiling, STARComm bridges the gap between spatial biology and clinical translation, advancing the field of spatial medicine. SUMMARY: Despite major advances in spatial biology, no framework has yet linked spatially resolved intercellular communication networks, independent of cell types, to clinical outcomes in human disease. Here, we present STARComm, a scalable method that identifies Multicellular Interaction MCIMs (MCIMs). Applying STARComm to minor salivary gland biopsies from patients with chronic graft-versus-host disease (GVHD), we identify MCIMs that not only distinguish healthy from diseased tissue but also stratify patient survival. High-risk MCIMs are enriched for actionable immune and stromal pathways, including those targetable with existing therapies. These findings establish the first outcome-linked spatial communication framework in any human disease and highlight the translational potential of oral tissues as minimally invasive platforms for real-time immune diagnostics, prognostic modeling, and therapeutic screening.