A central task in virtual cell modeling is predicting single-cell transcriptional responses to unseen genetic perturbations and drug combinations, and biological networks provide valuable priors on gene relationships. Existing graph-based models commonly use the same network to structure gene representations and mediate intergene interactions, thereby implicitly treating stable associations as perturbation-response pathways. Gene Ontology and control-derived coexpression networks encode relatively stable relationships rather than intervention-specific response directions or magnitudes. We therefore propose GeneGeoFlow, which conditions a control-anchored residual flow on gene-wise geometry derived from biological networks to learn intervention-specific transcriptional responses. GeneGeoFlow derives multi-scale spectral coordinates from Gene Ontology and control-derived coexpression networks. A perturbation-conditioned, gene-wise gating module selects relevant structural scales and network sources, yielding intervention-specific gene geometry. The resulting geometry conditions a control-anchored residual flow without explicitly propagating target-derived signals along the graph. Condition-wise optimal transport couples unpaired control and perturbed populations for training, while a Delta-correlation objective aligns the predicted and observed condition-level expression-shift directions. GeneGeoFlow achieves Pearson Delta scores of 0.8979 on the Norman additive benchmark and 0.9088 on five held-out drug combinations in the fixed ComboSciPlex test split. These results support perturbation-conditioned gene geometry as an effective structural prior for intervention-specific response prediction, without conflating stable gene relationships with response propagation.
Predicting cellular transcriptional responses to genetic perturbations is a central problem in single-cell biology, especially in the zero-shot setting where the perturbed gene or gene combination is unseen during training. A major difficulty is that perturbation effects are not determined by expression state alone: they depend on how the perturbed gene product influences other genes and proteins, how those downstream factors act on cis-regulatory elements, and which regulatory programs are active in the current cell state. To better capture this biological complexity, we propose CisTransCell, a cell-conditioned multi-modal framework for single-cell perturbation prediction that augments each gene with two complementary priors: a regulatory-sequence prior that captures how the gene is controlled, and a coding-sequence prior that captures what the gene product does. By integrating these priors with cellular expression state, CisTransCell models perturbation response as a cascade from gene function to regulatory control to downstream transcriptional change. Experiments on benchmark single-cell perturbation datasets show that CisTransCell achieves strong performance in zero-shot perturbation prediction.
Predicting transcriptional responses to genetic perturbations could reduce the experimental burden of functional genomics, but extrapolation to genes that were never perturbed during training remains difficult. We present Stable-Shift, a structured method for estimating unseen-gene responses. Stable-Shift aggregates single-cell measurements into perturbation-level expression shifts, fits a low-rank response basis using training perturbations only, and predicts an unseen gene's coordinates in that basis from biological context. The context combines STRING interactions, network structure, control-cell expression statistics, and Gene Ontology annotations; the evaluated implementation uses graph convolution to integrate these inputs. On the supplied K562 Perturb-seq benchmark, Stable-Shift obtained 0.592 cosine similarity, compared with 0.569 for GEARS, together with higher Spearman correlation and top-gene precision among the evaluated methods. Its mean cosine similarity over five unseen-gene splits was 0.589 +/- 0.008. The same ordering was observed in the supplied graph-aware, residualized, gene-space, and Norman-dataset comparisons. These results support further study of biologically structured latent-response prediction, while the lower gene-space accuracy and sensitivity to sparse graph neighborhoods limit the scope of the present conclusions.
Virtual-cell models aim to predict how cell populations respond to perturbations, but control and treated cells are measured as unpaired populations, complicating the learning of perturbation-specific effects. We present SCALE, a conditional transport model that represents cells as unordered sets and predicts treated populations without cell-level matching. A shared set-aware encoder and conditional DiT backbone learn latent transport, making endpoint supervision directly delta-aligned without an auxiliary delta objective. Across genetic, chemical, developmental and immune perturbations, SCALE recovered gene-expression changes, response directions and population structure. In CRISPR data with dominant cell-line effects, SCALE outperformed competing methods across seven metrics and maintained separation among gene-target representations rather than collapsing them into a shared region. SCALE further prioritized cytokines predicted to produce distinct immune activation and inflammatory responses. Experiments using matched PBMC samples from three donors confirmed these predicted differences. Together, SCALE enables perturbation-specific prediction from unpaired populations and supports experimental prioritization.