Chen, Jun

Abstract Coarsening Visium HD resolution from 8 to 64 µ m can flip cell-type co-localization from negative to positive ( r = −0.12 → +0.80 ), yet many widely used compositional deconvolution workflows require coarsening or subsampling at million-bin scale. Here we introduce FlashDeconv, which combines leverage-score importance sampling with sparse spatial regularization to achieve competitive benchmark accuracy while processing 1.6 million bins in 153 seconds on commodity hardware. Systematic multi-resolution analysis of Visium HD mouse intestine reveals a tissue-specific resolution horizon (8–16 µ m)—the scale at which this sign inversion occurs—validated by Xenium ground truth. Below this horizon, FlashDeconv provides, to our knowledge, the first sequencing-based quantification of Tuft cell chemosensory niches (15.3-fold stem cell enrichment). In a 1.6-million-bin human colorectal cancer cohort, FlashDeconv uncovers neutrophil inflammatory microdomains co-localized with immunoregulatory dendritic cells (mRegDC) at the tumor–stroma interface—spatial niches largely missed by discrete-label summaries, with RCTD doublet mode labeling only 2.3% of hotspot bins as neutrophil singlets.