We present an approach to denoising spatial transcriptomics images that is particularly effective for uncovering cell identities in the regime of ultra-low sequencing depths, and also allows for interpolation of gene expression. The method -- Spatial Transcriptomics via Adaptive Regularization and Kernels (STARK) -- augments kernel ridge regression with an incrementally adaptive graph Laplacian regularizer. In each iteration, we (1) perform kernel ridge regression with a fixed graph to update the image, and (2) update the graph based on the new image. The kernel ridge regression step involves reducing the infinite dimensional problem on a space of images to finite dimensions via a modified representer theorem. Starting with a purely spatial graph, and updating it as we improve our image makes the graph more robust to noise in low sequencing depth regimes. We show that the aforementioned approach optimizes a block-convex objective through an alternating minimization scheme wherein the sub-problems have closed form expressions that are easily computed. This perspective allows us to prove convergence of the iterates to a stationary point of this non-convex objective. Statistically, such stationary points converge to the ground truth with rate $\mathcal{O}(R^{-1/2})$ where $R$ is the number of reads. In numerical experiments on real spatial transcriptomics data, the denoising performance of STARK, evaluated in terms of label transfer accuracy, shows consistent improvement over the competing methods tested.

In multicellular organisms, cells coordinate their activities through cell-cell communication (CCC), which are crucial for development, tissue homeostasis, and disease progression. Recent advances in single-cell and spatial omics technologies provide unprecedented opportunities to systematically infer and analyze CCC from these omics data, either by integrating prior knowledge of ligand-receptor interactions (LRIs) or through de novo approaches. A variety of computational methods have been developed, focusing on methodological innovations, accurate modeling of complex signaling mechanisms, and investigation of broader biological questions. These advances have greatly enhanced our ability to analyze CCC and generate biological hypotheses. Here, we introduce the biological mechanisms and modeling strategies of CCC, and provide a focused overview of more than 140 computational methods for inferring CCC from single-cell and spatial transcriptomic data, emphasizing the diversity in methodological frameworks and biological questions. Finally, we discuss the current challenges and future opportunities in this rapidly evolving field.

Artificial Intelligence Virtual Cells (AIVCs) aim to learn executable, decision-relevant models of cell state from multimodal, multiscale measurements. Recent studies have introduced single-cell and spatial foundation models, improved cross-modality alignment, scaled perturbation atlases, and explored pathway-level readouts. Nevertheless, although held-out validation is standard practice, evaluations remain predominantly within single datasets and settings; evidence indicates that transport across laboratories and platforms is often limited, that some data splits are vulnerable to leakage and coverage bias, and that dose, time and combination effects are not yet systematically handled. Cross-scale coupling also remains constrained, as anchors linking molecular, cellular and tissue levels are sparse, and alignment to scientific or clinical readouts varies across studies. We propose a model-agnostic Cell-State Latent (CSL) perspective that organizes learning via an operator grammar: measurement, lift/project for cross-scale coupling, and intervention for dosing and scheduling. This view motivates a decision-aligned evaluation blueprint across modality, scale, context and intervention, and emphasizes function-space readouts such as pathway activity, spatial neighborhoods and clinically relevant endpoints. We recommend operator-aware data design, leakage-resistant partitions, and transparent calibration and reporting to enable reproducible, like-for-like comparisons.

Spatial Transcriptomics enables mapping of gene expression within its native tissue context, but current platforms measure only a limited set of genes due to experimental constraints and excessive costs. To overcome this, computational models integrate Single-Cell RNA Sequencing data with Spatial Transcriptomics to predict unmeasured genes. We propose CASPER, a cross-attention based framework that predicts unmeasured gene expression in Spatial Transcriptomics by leveraging centroid-level representations from Single-Cell RNA Sequencing. We performed rigorous testing over four state-of-the-art Spatial Transcriptomics/Single-Cell RNA Sequencing dataset pairs across four existing baseline models. CASPER shows significant improvement in nine out of the twelve metrics for our experiments. This work paves the way for further work in Spatial Transcriptomics to Single-Cell RNA Sequencing modality translation. The code for CASPER is available at https://github.com/AI4Med-Lab/CASPER.

Spatial transcriptomics is an emerging field that enables the identification of functional regions based on the spatial distribution of gene expression. Integrating this functional information present in transcriptomic data with structural data from histopathology images is an active research area with applications in identifying tumor substructures associated with cancer drug resistance. Current histopathology-spatial-transcriptomic region segmentation methods suffer due to either making spatial transcriptomics prominent by using histopathology features just to assist processing spatial transcriptomics data or using vanilla contrastive learning that make histopathology images prominent due to only promoting common features losing functional information. In both extremes, the model gets either lost in the noise of spatial transcriptomics or overly smoothed, losing essential information. Thus, we propose our novel architecture SENCA-st (Shared Encoder with Neighborhood Cross Attention) that preserves the features of both modalities. More importantly, it emphasizes regions that are structurally similar in histopathology but functionally different on spatial transcriptomics using cross-attention. We demonstrate the superior performance of our model that surpasses state-of-the-art methods in detecting tumor heterogeneity and tumor micro-environment regions, a clinically crucial aspect.

The rapid advancement of spatial transcriptomics (ST), i.e., spatial gene expressions, has made it possible to measure gene expression within original tissue, enabling us to discover molecular mechanisms. However, current ST platforms frequently suffer from low resolution, limiting the in-depth understanding of spatial gene expression. Super-resolution approaches promise to enhance ST maps by integrating histology images with gene expressions of profiled tissue spots. However, it remains a challenge to model the interactions between histology images and gene expressions for effective ST enhancement. This study presents a cross-modal cross-content contrastive diffusion framework, called C3-Diff, for ST enhancement with histology images as guidance. In C3-Diff, we firstly analyze the deficiency of traditional contrastive learning paradigm, which is then refined to extract both modal-invariant and content-invariant features of ST maps and histology images. Further, to overcome the problem of low sequencing sensitivity in ST maps, we perform nosing-based information augmentation on the surface of feature unit hypersphere. Finally, we propose a dynamic cross-modal imputation-based training strategy to mitigate ST data scarcity. We tested C3-Diff by benchmarking its performance on four public datasets, where it achieves significant improvements over competing methods. Moreover, we evaluate C3-Diff on downstream tasks of cell type localization, gene expression correlation and single-cell-level gene expression prediction, promoting AI-enhanced biotechnology for biomedical research and clinical applications. Codes are available at https://github.com/XiaofeiWang2018/C3-Diff.

HEST -1k processing enabled the identification of 2.1 million expression-morphology pairs and over 76 million nuclei.

Recent advances in multi-modal algorithms have driven and been driven by the increasing availability of large image-text datasets, leading to significant strides in various fields, including computational pathology.