Gene Expression Prediction from Histopathology Images

The high cost of spatial transcriptomics (ST) has driven extensive studies into predicting gene expression directly from H&E histology images. However, this prediction task faces an inherent limitation, as tissue morphology alone provides insufficient information to fully resolve underlying gene expression. To address this limitation, a recent study leverages partial gene expression to guide the prediction process alongside histology images. Building on this paradigm, we approach the prediction task as a spatial imputation problem, employing a Masked Autoencoder (MAE) to utilize a small fraction of gene expression as genetic anchors for inferring whole-slide gene expression profiles. Specifically, we propose a bio-saliency score and a learning-to-rank strategy to adaptively identify the most informative spots within the tissue. Based on these identified spots, our framework selects contiguous regions as genetic anchors to ensure suitability for real-world ST profiling hardware. To effectively leverage these anchors, we design a cross-modal joint encoder that integrates visual and genetic modalities. By aligning the selected anchors with their corresponding visual features via contrastive learning, the encoder generates robust joint representations to accurately predict gene expression across the whole slide. Notably, our framework consistently surpasses existing methods in both histology-only prediction and spatial imputation, achieving superior accuracy even without genetic anchors and further excelling with as little as 10% transcriptomic coverage. Our code is available at https://github.com/Kyyle2114/CAMMST.

Spatial transcriptomics (ST) links gene expression with tissue morphology but remains expensive and low-throughput, motivating surrogates that infer expression from routine histology. Whole-slide H&E-to-ST inference pairs a gigapixel image with gene measurements at a sparse, irregular set of locations, making multiscale modeling challenging without incurring dense-grid overhead or quadratic token mixing. We propose HiST, a hierarchical sparse transformer that treats measured locations as a lattice-indexed sparse field and builds a dyadic encoder--decoder directly on the active tissue footprint. HiST combines sparse window attention for local geometric correspondence with resolution-changing operators for rapid multiscale context integration. For a fixed window size, the dominant runtime and memory scale with the number of observed locations rather than the dense slide area. To mitigate slide-specific acquisition variation, HiST adds a bottlenecked global conditioning pathway via a slide calibration token that summarizes slide-level context and conditions local representations. On a multi-organ benchmark spanning diverse tissues and acquisition sources, HiST improves predictive performance over recent baselines while reducing runtime and peak memory.

Histology-based single-cell spatial transcriptomics (ST) estimation aims to predict gene expression for individual cells from histopathological images and cell locations, reducing the need for costly single-cell ST measurements. Unlike existing histology-to-ST methods that mainly predict spot-level profiles for local regions containing multiple cells, this task requires modeling cell-to-cell expression variability, which is strongly structured by cell type. We propose Genomics-Guided Cell-Type-Specific Mixture-of-Experts (GC-MoE), which estimates cell-type probabilities with a routing network and softly combines cell-type-specific experts for gene expression prediction. To further encode cell-type-dependent gene programs, we introduce the Cell-Type-Specific Co-Expression-Aware Predictor (CAP), together with a lightweight Cell-to-Cell Interaction Attention (C2CA) module for neighboring-cell context. Experiments and ablations on public single-cell ST datasets show consistent improvements over existing single-cell and adapted spot-level baselines.

Predicting spatial gene expression from routine H&E enables large-scale molecular profiling, yet current models treat this as isolated pointwise tasks, thereby overlooking essential biological structures like gene coordination and spatial distribution. To preserve these relationships, we introduce FLAG, a diffusion-based framework that redefines this task as structured distribution modeling. At the same time, we identify the critical Gene Dimension Curse, where joint modeling gene expression and their spatial interactions fail in high-dimensional spaces, and FLAG solves this challenge by integrating a spatial graph encoder for topological consistency and utilizing Gene Foundation Model (GFM) alignment for gene-gene fidelity in the generation process. To rigorously assess model performance, we propose a set of novel structural evaluation metrics, including Gene Structural Correlation (GSC) and Spatial Structural Correlation (SSC). Our experiments demonstrate that FLAG is highly competitive in traditional accuracy (PCC/MSE) while achieving significantly enhanced structural fidelity in capturing both gene-gene and gene-spatial relationships. The code is available at https://github.com/darkflash03/FLAG.

Histopathology whole-slide images (WSIs) are routinely acquired in clinical practice and contain rich tissue morphology but lack direct molecular architecture and functional programs defining pathological states, whereas RNA sequencing (RNA-seq) provides genome-wide transcriptional profiles at substantial cost, thereby motivating WSI-based genome-wide transcriptomic prediction. Existing approaches for predicting gene expression from WSIs predominantly rely on deterministic regression with one-to-one mapping, limiting their ability to capture biological heterogeneity and predictive uncertainty. We propose RNA-FM, a flow-matching generative framework for genome-wide bulk RNA-seq prediction from WSIs. RNA-FM formulates transcriptomic prediction as a continuous-time conditional transport problem, learning a velocity field that maps a simple prior to the target gene expression distribution conditioned on morphologies. By integrating pathway-level structure, RNA-FM enables scalable and biologically interpretable genome-wide gene expression imputation. Extensive experiments demonstrate that RNA-FM consistently outperforms state-of-the-art approaches while maintaining biological meaningfulness. Code is available at https://github.com/YXSong000/RNA-FM.

Spatial transcriptomics (ST) enables spatially resolved gene profiling but remains expensive and low-throughput, limiting large-cohort studies and routine clinical use. Predicting spatial gene expression from routine hematoxylin and eosin (H&E) slides is a promising alternative, yet under realistic leave-one-slide-out evaluation, existing models often suffer from slide-level appearance shifts and regression-driven over-smoothing that suppress biologically meaningful variation. CHRep is a two-phase framework for robust histology-to-expression prediction. In the training phase, CHRep learns a structure-aware representation by jointly optimizing correlation-aware regression, symmetric image-expression alignment, and coordinate-induced spatial topology regularization. In the inference phase, cross-slide robustness is improved without backbone fine-tuning through a lightweight calibration module trained on the training slides, which combines a non-parametric estimate from a training gallery with a magnitude-regularized correction module. Unlike prior embedding-alignment or retrieval-based transfer methods that rely on a single prediction route, CHRep couples topology-preserving representation learning with post-hoc calibration, enabling stable neighborhood retrieval and controlled bias correction under slide-level shifts. Across the three cohorts, CHRep consistently improves gene-wise correlation under leave-one-slide-out evaluation, with the largest gains observed on Alex+10x. Relative to HAGE, the Pearson correlation coefficient on all considered genes [PCC(ACG)] increases by 4.0% on cSCC and 9.8% on HER2+. Relative to mclSTExp, PCC(ACG) further improves by 39.5% on Alex+10x, together with 9.7% and 9.0% reductions in mean squared error (MSE) and mean absolute error (MAE), respectively.

Spatial transcriptomics (ST) enables gene expression mapping within anatomical context but remains costly and low-throughput. Hematoxylin and eosin (H&E) staining offers rich morphology yet lacks molecular resolution. We present \ours (Spatial Transcriptomics and histOlogy Representation Model), a foundation model trained on 1.2 million spatially resolved transcriptomic profiles with matched histology across 18 organs. Using a hierarchical architecture integrating morphological features, gene expression, and spatial context, STORM bridges imaging and omics through robust molecular--morphological representations. STORM enhances spatial domain discovery, producing biologically coherent tissue maps, and outperforms existing methods in predicting spatial gene expression from H&E images across 11 tumor types. The model is platform-agnostic, performing consistently across Visium, Xenium, Visium HD, and CosMx. Applied to 23 independent cohorts comprising 7,245 patients, STORM significantly improves immunotherapy response prediction and prognostication over established biomarkers, providing a scalable framework for spatially informed discovery and clinical precision medicine.

Spatial Transcriptomics (ST) provides spatially resolved gene expression profiles within intact tissue architecture, enabling molecular analysis in histological context. However, the high cost, limited throughput, and restricted data sharing of ST experiments result in severe data scarcity, constraining the development of robust computational models. To address this limitation, we present a Central-to-Local adaptive generative diffusion framework for ST (C2L-ST) that integrates large-scale morphological priors with limited molecular guidance. A global central model is first pretrained on extensive histopathology datasets to learn transferable morphological representations, and institution-specific local models are then adapted through lightweight gene-conditioned modulation using a small number of paired image-gene spots. This strategy enables the synthesis of realistic and molecularly consistent histology patches under data-limited conditions. The generated images exhibit high visual and structural fidelity, reproduce cellular composition, and show strong embedding overlap with real data across multiple organs, reflecting both realism and diversity. When incorporated into downstream training, synthetic image-gene pairs improve gene expression prediction accuracy and spatial coherence, achieving performance comparable to real data while requiring only a fraction of sampled spots. C2L-ST provides a scalable and data-efficient framework for molecular-level data augmentation, offering a domain-adaptive and generalizable approach for integrating histology and transcriptomics in spatial biology and related fields.

Spatial Transcriptomics (ST) provides spatially-resolved gene expression, offering crucial insights into tissue architecture and complex diseases. However, its prohibitive cost limits widespread adoption, leading to significant attention on inferring spatial gene expression from readily available whole slide images. While graph neural networks have been proposed to model interactions between tissue regions, their reliance on pre-defined sparse graphs prevents them from considering potentially interacting spot pairs, resulting in a structural limitation in capturing complex biological relationships. To address this, we propose FEAST (Fully connected Expressive Attention for Spatial Transcriptomics), an attention-based framework that models the tissue as a fully connected graph, enabling the consideration of all pairwise interactions. To better reflect biological interactions, we introduce negative-aware attention, which models both excitatory and inhibitory interactions, capturing essential negative relationships that standard attention often overlooks. Furthermore, to mitigate the information loss from truncated or ignored context in standard spot image extraction, we introduce an off-grid sampling strategy that gathers additional images from intermediate regions, allowing the model to capture a richer morphological context. Experiments on public ST datasets show that FEAST surpasses state-of-the-art methods in gene expression prediction while providing biologically plausible attention maps that clarify positive and negative interactions. Our code is available at https://github.com/starforTJ/ FEAST.

While spatial transcriptomics (ST) has advanced our understanding of gene expression in tissue context, its high experimental cost limits its large-scale application. Predicting ST from pathology images is a promising, cost-effective alternative, but existing methods struggle to capture complex cross-slide spatial relationships. To address the challenge, we propose SpaHGC, a multi-modal heterogeneous graph-based model that captures both intra-slice and inter-slice spot-spot relationships from histology images. It integrates local spatial context within the target slide and cross-slide similarities computed from image embeddings extracted by a pathology foundation model. These embeddings enable inter-slice knowledge transfer, and SpaHGC further incorporates Masked Graph Contrastive Learning to enhance feature representation and transfer spatial gene expression knowledge from reference to target slides, enabling it to model complex spatial dependencies and significantly improve prediction accuracy. We conducted comprehensive benchmarking on seven matched histology-ST datasets from different platforms, tissues, and cancer subtypes. The results demonstrate that SpaHGC significantly outperforms the existing nine state-of-the-art methods across all evaluation metrics. Additionally, the predictions are significantly enriched in multiple cancer-related pathways, thereby highlighting its strong biological relevance and application potential.

Spatial transcriptomics (ST) enables spot-level in situ expression profiling, but its high cost and limited throughput motivate predicting expression directly from HE-stained histology. Recent advances explore using score- or flow-based generative models to estimate the conditional distribution of gene expression from histology, offering a flexible alternative to deterministic regression approaches. However, most existing generative approaches omit explicit modeling of gene-gene dependencies, undermining biological coherence. Single-cell foundation models (sc-FMs), pre-trained across diverse cell populations, capture these critical gene relationships that histology alone cannot reveal. Yet, applying expression-only sc-FMs to histology-conditioned expression modeling is nontrivial due to the absence of a visual pathway, a mismatch between their pre-training and conditional ST objectives, and the scarcity of mixed-cell ST supervision. To address these challenges, we propose HINGE (HIstology-coNditioned GEneration), which retrofits a pre-trained sc-FM into a conditional expression generator while mostly preserving its learned gene relationships. We achieve this by introducing SoftAdaLN, a lightweight, identity-initialized modulation that injects layer-wise visual context into the backbone, coupled with an expression-space masked diffusion objective and a warm-start curriculum to ensure objective alignment and training stability. Evaluated on three ST datasets, ours outperforms state-of-the-art baselines on mean Pearson correlation and yields more accurate spatial marker expression patterns and higher pairwise co-expression consistency, establishing a practical route to adapt pre-trained sc-FMs for histology-conditioned spatial expression generation.

Estimating slide- and patch-level gene expression profiles from pathology images enables rapid and low-cost molecular analysis with broad clinical impact. Despite strong results, existing approaches treat gene expression as a mere slide- or spot-level signal and do not incorporate the fact that the measured expression arises from the aggregation of underlying cell-level expression. To explicitly introduce this missing cell-resolved guidance, we propose a Cell-type Prototype-informed Neural Network (CPNN) that leverages publicly available single-cell RNA-sequencing datasets. Since single-cell measurements are noisy and not paired with histology images, we first estimate cell-type prototypes-mean expression profiles that reflect stable gene-gene co-variation patterns.CPNN then learns cell-type compositional weights directly from images and models the relationship between prototypes and observed bulk or spatial expression, providing a biologically grounded and structurally regularized prediction framework. We evaluate CPNN on three slide-level datasets and three patch-level spatial transcriptomics datasets. Across all settings, CPNN achieves the highest performance in terms of Spearman correlation. Moreover, by visualizing the inferred compositional weights, our framework provides interpretable insights into which cell types drive the predicted expression. Code is publicly available at https://github.com/naivete5656/CPNN.

Cancer pathological analysis requires modeling tumor heterogeneity across multiple modalities, primarily through transcriptomics and whole slide imaging (WSI), along with their spatial relations. On one hand, bulk transcriptomics and WSI images are largely available but lack spatial mapping; on the other hand, spatial transcriptomics (ST) data can offer high spatial resolution, yet facing challenges of high cost, low sequencing depth, and limited sample sizes. Therefore, the data foundation of either side is flawed and has its limit in accurately finding the mapping between the two modalities. To this end, we propose BiTro, a bidirectional transfer learning framework that can enhance bulk and spatial transcriptomics prediction from pathological images. Our contributions are twofold. First, we design a universal and transferable model architecture that works for both bulk+WSI and ST data. A major highlight is that we model WSI images on the cellular level to better capture cells' visual features, morphological phenotypes, and their spatial relations; to map cells' features to their transcriptomics measured in bulk or ST, we adopt multiple instance learning. Second, by using LoRA, our model can be efficiently transferred between bulk and ST data to exploit their complementary information. To test our framework, we conducted comprehensive experiments on five cancer datasets. Results demonstrate that 1) our base model can achieve better or competitive performance compared to existing models on bulk or spatial transcriptomics prediction, and 2) transfer learning can further improve the base model's performance.

Pathology foundation models learn morphological representations through self-supervised pretraining on large-scale whole-slide images, yet they do not explicitly capture the underlying molecular state of the tissue. Spatial transcriptomics technologies bridge this gap by measuring gene expression in situ, offering a natural cross-modal supervisory signal. We propose MINT (Molecularly Informed Training), a fine-tuning framework that incorporates spatial transcriptomics supervision into pretrained pathology Vision Transformers. MINT appends a learnable ST token to the ViT input to encode transcriptomic information separately from the morphological CLS token, preventing catastrophic forgetting through DINO self-distillation and explicit feature anchoring to the frozen pretrained encoder. Gene expression regression at both spot-level (Visium) and patch-level (Xenium) resolutions provides complementary supervision across spatial scales. Trained on 577 publicly available HEST samples, MINT achieves the best overall performance on both HEST-Bench for gene expression prediction (mean Pearson r = 0.440) and EVA for general pathology tasks (0.803), demonstrating that spatial transcriptomics supervision complements morphology-centric self-supervised pretraining.

Foundation models have recently achieved impressive success in computational pathology, demonstrating strong generalization across diverse histopathology tasks. However, existing models overlook the heterogeneous and non-uniform organization of pathological regions of interest (ROIs) because they rely on natural image backbones not tailored for tissue morphology. Consequently, they often fail to capture the coherent tissue architecture beyond isolated patches, limiting interpretability and clinical relevance. To address these challenges, we present Cross-modal Adaptive Region Encoder (CARE), a foundation model for pathology that automatically partitions WSIs into several morphologically relevant regions. Specifically, CARE employs a two-stage pretraining strategy: (1) a self-supervised unimodal pretraining stage that learns morphological representations from 34,277 whole-slide images (WSIs) without segmentation annotations, and (2) a cross-modal alignment stage that leverages RNA and protein profiles to refine the construction and representation of adaptive regions. This molecular guidance enables CARE to identify biologically relevant patterns and generate irregular yet coherent tissue regions, selecting the most representative area as ROI. CARE supports a broad range of pathology-related tasks, using either the ROI feature or the slide-level feature obtained by aggregating adaptive regions. Based on only one-tenth of the pretraining data typically used by mainstream foundation models, CARE achieves superior average performance across 33 downstream benchmarks, including morphological classification, molecular prediction, and survival analysis, and outperforms other foundation model baselines overall.