Querying Counterfactuals on Tissue Graphs with Supervised Disentanglement

Tissue graph counterfactuals ask how a cell's expression would change under altered spatial contexts. Such queries are central to predicting cell behavior in tissues, but lack a unified definition, with existing methods targeting specific intervention types or treating cells as i.i.d. In this work, we first formalize tissue graph counterfactuals as a class of spatial interventions that either rewire connections between cells (edge perturbation) or modify the expression of their neighbors (node perturbation). We then introduce Cellina, a modeling framework that uses supervised disentanglement to decompose a cell's intrinsic state from its spatial context, using the latter as a conditioning input for counterfactual predictions. Across benchmarks spanning 2.5 million spatially-resolved cells in colorectal cancer and mouse brain, Cellina outperforms spatially-informed and non-spatial competitors in counterfactual predictions, disentanglement, and scalability. Additionally, we show that Cellina reveals biologically distinct cancer subdomains in an unsupervised manner and enables targeted neighbor perturbation simulations.