HistoLoop: Iterative Contextual Inference with a Looped Transformer for Histology-Based Spatial Gene Expression Prediction

Overview & Synopsis

Predicting spatial gene expression from H&E images offers a scalable complement to experimental spatial transcriptomics. However, despite progress in spatial context modeling, how to construct subsequent context from spot states updated by earlier contextual interactions remains underexplored. We introduce HistoLoop, a looped Transformer that formulates prediction as iterative contextual inference. At each refinement step, HistoLoop aggregates the current spot states into context tokens at the corresponding resolution, processes them with a shared spatial Transformer, and retrieves spot-specific contextual information through cross-attention. A memory-mediated update integrates this information into persistent spot states, which are then used to construct context at the next, finer resolution. Under the HEST-Bench HVG50 evaluation protocol, HistoLoop achieves the highest macro-averaged gene-wise Pearson correlation among the compared methods across six cancer-specific tasks spanning five organs in HEST-1K. Ablation studies support the importance of recurrent state refinement and reconstructing context from updated spot states at progressively finer resolutions. Expression-derived clustering further suggests that HistoLoop better captures spatially organized multigene patterns.