VOICE: A Vision-Omics Foundation Model Integrating Direct and Retrieval-Based Prediction of In-situ Single-Cell Gene Expression

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.

Inferring spatially resolved gene expression from histology images offers a cost-effective complement to spatial transcriptomics (ST). However, existing methods reduce this task to a simple morphology-to-expression mapping, where visual similarity does not guarantee molecular consistency. Meanwhile, single-cell data has amassed rich resources far surpassing the scale of ST data, yet it remains underexplored in vision-omics modeling. Furthermore, current approaches commit to a monolithic paradigm with bottlenecks, unable to balance expressive flexibility with biological fidelity. To bridge these gaps, we propose DUET, a novel dual-paradigm framework that synergizes parametric prediction and memory-based retrieval under cellular inductive priors. DUET implements a parallel regression-retrieval paradigm, adaptively reconciling the outputs of its complementary pathways. To mitigate aleatoric vision ambiguity, we incorporate large-scale single-cell references to impose molecular states as biological constraints for faithful learning. Building upon structural refinement, we further design a lightweight adapter to dynamically assign branch preference across spatial contexts to achieve optimal performance. Extensive experiments on three public datasets across varied gene scales demonstrate that DUET achieves SOTA performance, with consistent gains contributed by each proposed component. Code is available at https://github.com/Junchao-Zhu/DUET

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 \emph{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.