Decoding Multicellular Communication Motifs from Spatial Transcriptomics with ALARMIST

Cellular organization is driven by recurrent, coordinated interactions between multiple cell types, each sending and receiving multiple signals. Existing computational methods for spatial profiling data consider only individual ligand-receptor interactions and fail to capture the higher-order interactions governing the tissue microenvironment. To address this gap, we developed ALARMIST (Assessment of Ligand And Receptor Motifs And Impacts in Spatial Transcriptomics), a probabilistic framework that infers interpretable multicellular communication patterns from spatial data. ALARMIST decomposes neighborhood-level signaling patterns into motifs: recurrent communication subnetworks involving multiple cell types and sets of enriched ligand-receptor interactions. For each cell, ALARMIST identifies its active motifs and estimates the downstream phenotypic effects of each motif on active cells. We applied alarmist to spatial datasets of lung adenocarcinoma (LUAD) and glioblastoma (GBM) to identify microenvironmental drivers of tumor progression. In paired LUAD and adenocarcinoma-in-situ (AIS) samples, ALARMIST identified an immune-active vascular motif at the tumor-normal boundary and implicated motif-active plasmacytoid dendritic cells as drivers of inflammation in early carcinogenesis. In matched low- and high-grade glioma samples, ALARMIST identified a hub-and-spoke motif centered on a malignant macrophage subpopulation, implicating a GRN-SORT1 signaling axis with a downstream impact gene set predictive of survival in low-grade glioma patients. Code for ALARMIST is available at https://github.com/tansey-lab/alarmist.