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arXiv · 2601.21560

HistoPrism: Unlocking Functional Pathway Analysis from Pan-Cancer Histology via Gene Expression Prediction

Susu Hu·Qinghe Zeng·Nithya Bhasker·Jakob Nikolas Kather·Stefanie Speidel
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Abstract

Predicting spatial gene expression from H&E histology offers a scalable and clinically accessible alternative to sequencing, but realizing clinical impact requires models that generalize across cancer types and capture biologically coherent signals. Prior work is often limited to per-cancer settings and variance-based evaluation, leaving functional relevance underexplored. We introduce HistoPrism, an efficient transformer-based architecture for pan-cancer prediction of gene expression from histology. To evaluate biological meaning, we introduce a pathway-level benchmark, shifting assessment from isolated gene-level variance to coherent functional pathways. HistoPrism not only surpasses prior state-of-the-art models on highly variable genes , but also more importantly, achieves substantial gains on pathway-level prediction, demonstrating its ability to recover biologically coherent transcriptomic patterns. With strong pan-cancer generalization and improved efficiency, HistoPrism establishes a new standard for clinically relevant transcriptomic modeling from routinely available histology.

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Susu Hu, Qinghe Zeng, Nithya Bhasker, Jakob Nikolas Kather, Stefanie Speidel. 2026-02-09. HistoPrism: Unlocking Functional Pathway Analysis from Pan-Cancer Histology via Gene Expression Prediction. https://arxiv.org/abs/2601.21560

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