Spatial tumor evolution panorama of ovarian cancer.

Ovarian cancer is an aggressive disease characterized by intraperitoneal dissemination and a distinctive microenvironment. By generating metastatic cohorts encompassing approximately 60 pairs of whole-genome and RNA sequencing, 100 single-cell samples, and 2.5 million spatial transcriptomics (ST) spots, we delineate site-specific tumor-host colocalization patterns. Utilizing our STARLETS framework, we elucidate a Darwinian evolutionary trajectory in which hypoxia and immune pressures select for clones that eventually metastasize. High-resolution ST and ultimate dimensional imaging of solvent-cleared organs (uDISCO) imaging further identify a tripartite ensemble comprising MMP11+ myCAFs, epithelial cells, and SPP1+ macrophages in ascites and metastases, which can be modulated via SPP1-CD44 inhibition. SPP1+ macrophages predict therapeutic responses in clinical trials, including oncolytic virus and poly(ADP-ribose) polymerase inhibitor treatments. Collectively, our study advances insights into spatial dynamics that hold promise for therapeutic approaches in ovarian cancer.