ST-Prompt Guided Histological Hypergraph Learning for Spatial Gene Expression Prediction

Spatial Transcriptomics (ST) reveals the spatial distribution of gene expression in tissues, offering critical insights into biological processes and disease mechanisms. However, predicting ST from H\&E-stained histology images is challenging due to the heterogeneous relationship between histomorphology and gene expression, which arises from substantial variability across different patients and tissue sections. A more practical and valuable approach is to utilize ST data from a few local regions to predict the spatial transcriptomic landscape across the remaining regions in H&E slides. In response, we propose PHG2ST, an ST-prompt guided histological hypergraph learning framework, which leverages sparse ST signals as prompts to guide histological hypergraph learning for global spatial gene expression prediction. Our framework fuses histological hypergraph representations at multiple scales through a masked ST-prompt encoding mechanism, improving robustness and generalizability. Benchmark evaluations on two public ST datasets demonstrate that PHG2ST outperforms the existing state-of-the-art methods and closely aligns with the ground truth. These results underscore the potential of leveraging sparse local ST data for scalable and cost-effective spatial gene expression mapping in real-world biomedical applications.