Samaran, J.; Peyre, G.; Cantini, L.

Fully capturing cellular identity requires integrating multiple molecular layers. Bridge integration, i.e. aligning unimodal datasets using a paired multi-omic reference, has emerged as a practical solution, yet existing methods offer limited interpretability and use paired information without regularization, making them sensitive to limited size and coverage. We introduce CHAMPOLLION, which uses regularized optimal transport to learn an interpretable cross-modal metric that drives the alignment of unpaired cells while capturing relationships between molecular features. Benchmarks on RNA-protein and RNA-ATAC datasets show that CHAMPOLLION outperforms existing approaches, remaining accurate with few paired cells and even generalizing to unseen cell types. Beyond alignment, CHAMPOLLION reveals biologically meaningful cross-modal relationships, highlighting in scRNA-protein data a potential role for CD18 across multiple cancers, and, in a human tonsil atlas combining scRNA-seq and scATAC-seq, suggesting that MEF2C may regulate inflammatory responses beyond the brain, notably in plasmacytoid dendritic cells.