BioKERN: Biological Kernel Regularization for Histology-to-Transcriptomics Neighborhood Retrieval

Spatial transcriptomics provides a molecularly rich description of tissue organization, enabling unsupervised discovery of tissue niches -- spatially coherent regions of distinct cell-type composition and function that are relevant to both biological research and clinical interpretation. However, spatial transcriptomics remains costly and scarce, while H&E histology is abundant but carries a less granular signal. We propose to leverage paired spatial transcriptomics and H&E data to transfer transcriptomics-derived niche structure to a histology-only model via cross-modal distillation. Across multiple tissue types and disease contexts, the distilled model achieves substantially higher agreement with transcriptomics-derived niche structure than unsupervised morphology-based baselines trained on identical image features, and recovers biologically meaningful neighborhood composition as confirmed by cell-type analysis. The resulting framework leverages paired spatial transcriptomic and H&E data during training, and can then be applied to held-out tissue regions using histology alone, without any transcriptomic input at inference time.

Spatial transcriptomics (ST) links tissue morphology with molecular programs, motivating multimodal pretraining methods that align histology images with gene expression. However, existing approaches suffer from two key limitations: spatially informative gene selection is often dominated by ubiquitous housekeeping genes, leading to weakly discriminative representations, and independent spot-patch alignment fails to capture spatial dependencies that are critical for tissue organization. To address these challenges, we introduce PaSTel, a hierarchical multimodal pretraining framework that integrates biological priors at three levels. At the spot level, TF-IDF reweighting is used to identify spatially informative genes; at the functional level, curated KEGG pathways serve as anchors for encoding global biological semantics; and at the regional level, spatial clustering aggregates neighboring spots to model meso-scale tissue structure. Across multiple downstream tasks, PaSTel consistently outperforms existing vision and vision-omics encoders, demonstrating that incorporating multiscale biological priors yields more informative and transferable representations for spatial transcriptomics.

Spatial transcriptomics provides spatially resolved molecular profiling, but its cost, limited throughput and experimental complexity hinder routine large-scale use. Predicting spatial gene expression from hematoxylin-and-eosin-stained histology images offers a scalable alternative, yet remains challenging because histology provides only an indirect morphological view of molecular activity. Existing methods typically decode expression from visual features in a single stage, even when enhanced with spatial aggregation, retrieval or multi-resolution fusion. This formulation is restrictive because spot-level expression reflects not only local morphology but also cellular identity, neighborhood composition and tissue-level organization. We propose BCARP, a Biology-guided Context-Aware Residual Propagation framework for histology-guided spatial transcriptomics prediction. Instead of directly predicting gene expression from histology embeddings, BCARP treats them as morphology visual priors and progressively refines spot representations in a transcriptomics-oriented latent space. Each refinement step integrates nuclei-guided local cellular context with prototype-guided global context propagation, enabling information exchange across both neighboring and spatially distant spots. A pattern-scale decoder further separates spatial expression into pattern prediction from raw expression with scale calibration. Evaluated on three ST datasets and ten HEST-1k cohorts, BCARP achieves the highest mean correlation-based performance against other baselines. Numerical results support biology-guided local-global residual propagation as an effective alternative to visual decoding for histology-to-transcriptomics prediction.