Parameters used by MMSpa.

Spatial transcriptome (ST) technologies have transformed the study of tissue structure by retaining the spatial distribution of gene expression. One major challenge in accurately identifying spatial domains is to extract domain-related information from spatial locations and gene expression. Here, we propose MMSpa, a masked graph attention autoencoder framework specifically designed to improve spatial domain identification. MMSpa incorporates an edge-removal strategy to construct an enhanced spatial graph to fundamentally address cross-domain interference and characterize clearer domain boundaries. By focusing on masked gene expression reconstruction, MMSpa learns stable latent representations that capture core biological features, facilitating the identification of similar spatial subdomains and detecting domain differences across biological samples at the same developmental stage. Comparative analyses using ST datasets from multiple ST technologies and platforms demonstrated that MMSpa outperforms existing methods across various accuracy assessments. Notably, MMSpa excels in challenging scenarios involving highly heterogeneous and complex tissues, and can reveal finer-grained functional tissue domains obscured by other methods. This superior capability positions MMSpa as a powerful tool for uncovering new biological insights and compensating for the lack of spatial annotation in histopathology.