STAG: Biologically guided spatial transcriptomics prediction via hypergraph learning

Spatial transcriptomics (ST) enables spatially resolved gene expression profiling within intact tissue sections. However, its widespread adoption is constrained by the high cost and low throughput of current sequencing-based protocols. This has motivated growing interest in computationally predicting gene expression directly from routinely acquired histology images. Existing methods are largely restricted to isolated 2D tissue slices and fail to capture richer spatial relationships or structured dependencies among spot-level gene expression profiles. In this paper, we propose STAG, a dual-branch framework for gene-aware expression prediction and spatial context modeling. A Query branch predicts ST expression for an individual target spot, while a Neighbor branch acts as an auxiliary branch to model structured relationships among multiple spots. By leveraging hypergraph learning, the Neighbor branch captures higher-order spatial and molecular dependencies, enabling unified modeling of both intra-slice and inter-slice relationships. This design supports standard 2D settings (a single slice) and naturally extends to 3D scenarios when adjacent tissue sections are available. Moreover, STAG leverages gene semantic information as biological guidance by encoding gene names with a foundation model, enabling coordinated gene-aware interactions beyond independent gene prediction. STAG achieves an average gain of 5.16% in PCC@250 across six datasets. Under highly variable gene selection, STAG maintains the lowest RMSE and highest PCC@50 across three datasets. The effectiveness of the learned representations is further demonstrated in pseudo-3D prediction and downstream cancer classification tasks. Code is available at https://github.com/MCPathology/STAG.