REST: Reliability-Guided Spatial Transcriptomics Supervision for Gene Expression Prediction from Histopathological HE-Stained Images

Spatial transcriptomics (ST) enables gene expression mapping within anatomical context but remains costly and low-throughput. Hematoxylin and eosin (H&E) staining offers rich morphology yet lacks molecular resolution. We present \ours (Spatial Transcriptomics and histOlogy Representation Model), a foundation model trained on 1.2 million spatially resolved transcriptomic profiles with matched histology across 18 organs. Using a hierarchical architecture integrating morphological features, gene expression, and spatial context, STORM bridges imaging and omics through robust molecular--morphological representations. STORM enhances spatial domain discovery, producing biologically coherent tissue maps, and outperforms existing methods in predicting spatial gene expression from H&E images across 11 tumor types. The model is platform-agnostic, performing consistently across Visium, Xenium, Visium HD, and CosMx. Applied to 23 independent cohorts comprising 7,245 patients, STORM significantly improves immunotherapy response prediction and prognostication over established biomarkers, providing a scalable framework for spatially informed discovery and clinical precision medicine.

Recent advances in pathology foundation models have enabled accurate prediction of spatial transcriptomics (ST) from routine H&E images. However, existing explainability methods for vision transformer (ViT)-based models are largely limited to local heatmaps and do not reveal how morphological concepts contribute to ST predictions. Here, we introduce an explainable framework that combines relevance propagation and concept discovery to link transcriptional programs to tissue morphology. We developed a ViT-based framework for virtual ST from H&E images that combines ViT-aware layer-wise relevance propagation with relaxed archetypal TopK sparse autoencoder-based concept discovery. This approach provides both local explanations and global insights into the morphological patterns associated with transcriptional programs. We applied the framework to colorectal cancer ST data from the HEST-1k cohort and evaluated its generalizability in TCGA COAD. Our architecture accurately predicts clinically relevant ST signatures and accompanying molecular phenotypes. Measured and predicted gene expression profiles reveal substantial spatial heterogeneity of the colorectal cancer subtypes iCMS2 and iCMS3 across a large number of samples. Spatially resolved and aggregated iCMS classification achieve weighted F1 scores of 0.872 and 0.819 (0.770 in TCGA COAD), respectively, and both stratify patient outcome. Beyond prediction, our framework establishes a relevance-based concept atlas linking molecular phenotypes to histopathological representations. Comparison of activation- with relevance-derived concepts demonstrates that relevances provide a more direct link between tissue morphology and downstream predictions. We establish a general strategy for concept-based explanation of spatial prediction, and our framework is readily applicable to a broad range of ViT-based pathology models.

Spatial Transcriptomics (ST) has transformed biomedical research by enabling the spatial mapping of gene expression across tissue sections. However, high operational costs, specialized equipment requirements, and sensitivity to experimental noise limit the accessibility and scalability of ST. Recent computer vision approaches aim to overcome these limitations by predicting spatial gene expression directly from histopathology images. While effective, current approaches often suffer from gene expression over-smoothing and overly uniform predictions across tissue regions, suggesting that further progress depends on learning representations that reflect the hierarchical and asymmetric structure of gene regulation and tissue morphology. To address these issues, we propose Hyperbolic Contrastive Learning with Entailment for Spatial Transcriptomics (HyCLoST), a hyperbolic contrastive learning model that captures the intrinsic hierarchical relationships within ST data. By leveraging hyperbolic geometry and a gene-to-image entailment loss, HyCLoST learns structured, biologically grounded representations that improve gene expression prediction accuracy, achieving a 6% reduction in MSE and an 8% increase in PCC across 26 ST datasets, over previous methods. Our source code is publicly available at https://github.com/BCV-Uniandes/HyCLoST