Geometry-First Generative Spatial Single-Cell Reconstruction

Single-cell RNA sequencing (scRNA-seq) profiles large numbers of cells but loses spatial context, whereas spatial transcriptomics (ST) preserves partial spatial structure at lower resolution. Most existing integration methods either deconvolve spot mixtures or map cells onto a measured spot lattice, which ties reconstructions to a fixed grid and slide-specific coordinate systems, a limitation that is especially problematic in unpaired settings. We propose GEARS, a geometry-first framework that reconstructs an intrinsic single-cell spatial geometry guided by ST, without relying on cell-type labels, histological images, or cell-to-spot assignment. GEARS first learns a domain-invariant expression encoder that aligns ST spots and dissociated cells, and then trains a permutation-equivariant generator with a diffusion-based refiner with EDM-style preconditioning to generate local spatial geometries under pose-invariant supervision derived from ST coordinates. At inference, GEARS reconstructs geometry on many overlapping subsets of scRNA-seq cells, aggregates predicted pairwise distances across subsets, and solves a global distance-geometry problem to obtain canonical two-dimensional coordinates and a dense distance matrix. Extensive quantitative and qualitative experiments, including cross-section generalization, show that GEARS consistently improves global distance preservation, local neighborhood fidelity, and spatial distribution alignment compared to strong spatial mapping and deconvolution baselines.