Single-cell spatial atlas of high-grade serous ovarian cancer uncovers MHC class II as a key predictor of spatial tumor ecosystems and clinical outcomes.

The tumor microenvironment in high-grade serous ovarian carcinoma (HGSC) is a complex network of malignant-host cell interactions, yet its orchestration remains poorly understood. We present a single-cell spatial atlas of metastatic HGSC from 280 patients, integrating high-dimensional imaging and molecular profiling. Analyzing 929 single-cell maps, we identify spatial domains with diverse cell compositions and show that immune cell co-infiltration at the tumor-stroma interface impacts clinical outcomes. Using CEFIIRA, we find that tumor cell MHCII expression is a key predictor of prolonged survival. Validation with deconvoluted, single-cell, and two distinct spatial transcriptomic datasets, along with immunopeptidomic analysis, confirms that MHCII expression correlates with immune activation, antigen presentation, and TCR clonality. Using a patient-derived immuno-oncology platform, we demonstrate that tumor MHCII expression associates with increased CD8+ T cell cytotoxicity after PD-1 blockade, while blocking MHCII inhibits this activation. Our atlas offers new insights into immune activation, potentially improving patient stratification in HGSC.