ILR-SMO: Iterative Latent Refinement for Robust Spatial Multi-Omics Integration

Abstract

Spatial multi-omics technologies jointly profile diverse molecular modalities with spatial context, providing a comprehensive view of cellular heterogeneity and tissue organization. To integrate spatial multi-omics data and identify spatial domains, a wide range of unsupervised methods has been proposed. However, recent approaches rely on single-step fusion, directly aggregating heterogeneous modalities into a shared representation, making embeddings sensitive to modality imbalance and measurement noise that are inherent to spatial multi-omics data, as well as unstable optimization under weak supervision. Here, we propose ILR-SMO (Iterative Latent Refinement for Spatial Multi-Omics), a unified self-supervised framework that reformulates multimodal integration as a stability-aware refinement process over a shared latent representation. Instead of single-step plain fusion, ILR-SMO progressively integrates modality-specific information through sequential updates, allowing information to be injected in a controlled manner. This incremental refinement enables later updates to correct or compensate for earlier deviations, resulting in more stable and robust representation learning under heterogeneous and noisy modalities. ILR-SMO further incorporates reliability-aware modality gating for adaptive modulation of modality contributions, and employs a joint objective to enforce spatial coherence while preventing representation collapse. Extensive experiments on five spatial multi-omics benchmarks demonstrate that ILR-SMO consistently outperforms seven state-of-the-art methods and exhibits strong robustness across diverse settings.