Virtual spatial transcriptomics from histopathology enables prognostic and therapeutic response prediction in cancer

Spatial transcriptomics reveals cellular heterogeneity, intercellular communication, and tissue organization, but its cost and limited accessibility restrict clinical use. Here, we present VISTA, a model that integrates multi-scale histological features and spatial context to infer spatial gene expression from H&E stained tissue images. Across leave one section out cross validation and independent validation, VISTA robustly predicted thousands of genes and outperformed state-of-the-art methods. Beyond expression reconstruction, VISTA enabled clinically relevant downstream analyses. In TCGA breast cancer samples, it identified survival-associated genes, stratified prognostic risk groups, and revealed adverse tumor-associated spatial subtypes. In our inhouse intrahepatic cholangiocarcinoma cohort, it preserved tumor normal organization and identified CLDN4 and CYP3A4 as complementary spatial biomarkers. In HER2+ breast cancer, it predicted pathological response to neoadjuvant trastuzumab-based therapy and linked response-associated regions to immune and cytokine related programs. These results support virtual spatial transcriptomics from routine histopathology for oncology applications.