Learning Interpretable Tumor Microenvironment Representations by Fitting Pan-Cancer Cell State–Niche Correlation

In the tumor microenvironment, a cell’s state is influenced by cell–cell interactions (CCIs) with neighboring cells in its niches. Identifying dysregulated CCIs that are associated with pathogenic processes pinpoints targets for drug discovery. Imaging-based spatial transcriptomics and single-cell RNA sequencing provide, respectively, single-cell spatial information and transcriptome-wide measurements needed to study CCIs, but neither modality provides both. Existing spatial transcriptomics foundation models also cannot effectively learn from spatially resolved single-cell data with full-transcriptome coverage, explicitly infer the CCI mechanisms driving cell state–niche associations, or be interpretable enough to support direct biological interpretations. Here, we present GITIII-scale, a hierarchical, interpretable pan-cancer spatial transcriptomics foundation model for TME representation learning that investigates cell state–niche associations and their underlying ligand–receptor (LR) signaling pathways. GITIII-scale uses transformers to model interactions between pairs of cells at defined spatial distances, an interpretable single-layer graph transformer without a feed-forward network to decompose how each gene in a receiver cell is influenced by each neighboring sender cell, and a graph transformer to generate cellular-neighborhood embeddings. Trained on our assembled pan-cancer database of specimen-matched scRNA-seq and imaging-based spatial transcriptomics datasets, GITIII-scale generated TME embeddings that recovered niche-associated state changes more accurately than existing spatial transcriptomics foundation models in cancer types unseen during training. A case study of an unseen breast cancer dataset further demonstrated the model’s interpretability by identifying potentially drug-targetable LR pathways associated with endothelial overgrowth and tumorigenesis.