The automated computational workflow QUICHE reveals structural definitions of antitumor responses in triple-negative...

Recent advances in spatial biology can reveal how tissue organization changes in disease; however, interpreting these datasets in a generalized, scalable way remains challenging. Existing computational approaches rely on pairwise comparisons or unsupervised clustering, which can lack statistical rigor and miss rare, clinically relevant cellular niches. Here we present QUICHE-an automated and scalable statistical framework designed to discover cellular niches differentially enriched in populations, histological structures or acellular regions. Using in silico models and spatial proteomic imaging of human tissues, we show that QUICHE can accurately detect low-prevalence, condition-specific niches, outperforming the next best algorithm threefold. To investigate how tumor structure influences recurrence risk in triple-negative breast cancer, we applied QUICHE to a multicenter spatial proteomics cohort of 314 primary tumor resections. We discovered niches consistently enriched in tumor border and extracellular-matrix-remodeling regions, including those associated with recurrence-free survival. These findings were validated in two independent cohorts, suggesting that antitumor responses are driven by coordinated engagement between innate and adaptive immune cells, rather than any single population. QUICHE is provided as an open-source Python package ( https://github.com/jranek/quiche ).