Deciphering Cellular Ecosystems Driving Tumor Progression and Immune Escape from Spatial Transcriptomics and Single-Cell with COMPOTES

Cell-cell communication is central to understanding the complex interactions within the tumor microenvironment. However, current methods fail to identify recurrent communication patterns across patient cohorts from spatial transcriptomics, as they are often limited to single samples or lack essential spatial context. Yet this is essential for understanding how local environments influence cell phenotype and states, and shape the entire cellular ecosystem.

We introduce a machine-learning approach that models local, spatially aware ligand-receptor interactions and uses matrix factorization to extract global multicellular programs from large cohorts representing the complex biology of cancer. Applied to a multimodal muscle-invasive bladder cancer cohort of 146 patients, it uncovered 45 communication programs defined by distinct ligand-receptor pairs and cellular niches. In particular, we identified a conserved immune program linked to stalled anti-tumor immunity and a program linking KMT2D loss-of-function mutations with early-stage (T2) tumors, intense proliferation and a favorable response to neoadjuvant chemotherapy.