SAGE-FM: A lightweight and interpretable spatial transcriptomics foundation model.

Spatial transcriptomics enables spatial gene expression profiling, motivating computational models that capture spatially conditioned regulatory relationships. We introduce SAGE-FM, a lightweight spatial transcriptomics foundation model based on graph convolutional networks (GCN) trained with a masked-central-spot prediction objective. Trained on 416 human Visium samples spanning 15 organs, SAGE-FM learns spatially coherent embeddings that recover masked genes robustly, with 91% of masked genes showing significant correlations (p < 0.05). The SAGE-FM generated embeddings outperform MOFA and spatial transcriptomics in unsupervised clustering and preservation of biological heterogeneity. SAGE-FM generalizes to downstream tasks, enabling 81% accuracy in pathologist-defined spot annotation in oropharyngeal squamous cell carcinoma and improving glioblastoma subtype prediction relative to MOFA. <i>In silico</i> perturbation experiments further show that the model captures directional ligand-receptor and upstream-downstream regulatory effects consistent with ground truth. These results demonstrate that simple, parameter-efficient GCNs can serve as biologically interpretable and spatially aware foundation models for large-scale spatial transcriptomics.