StateXDiff: Cell State-Contextualized Multimodal Diffusion for Single-Cell Perturbation Prediction

TL;DR

StateXDiff is a novel multimodal diffusion framework that predicts single-cell drug responses by integrating transcriptomic and protein data, improving generalization under challenging conditions.

Contribution

It introduces a cell state-contextualized multimodal diffusion model with disentangled representations and mechanism-aware drug templates for better prediction accuracy.

Findings

Outperforms existing models in unseen cell line predictions.

Effectively models combinatorial drug perturbations.

Enhances generalization to out-of-distribution conditions.

Abstract

Predicting drug-induced cellular state changes at single-cell resolution remains a central challenge in virtual cell modeling, particularly under out-of-distribution (OOD) conditions. Current approaches predominantly rely on RNA-based assays, which often fail to adequately capture the diverse cellular states underlying drug responses. Moreover, conditional distribution shifts and low signal-to-noise ratios frequently cause models to learn spurious correlations rather than genuine state transitions. To address these limitations, we introduce StateXDiff, a cell State-contextualized multimodal (X) Diffusion framework for predicting single-cell responses to drug perturbations. The framework operates sequentially: first, it learns a disentangled, multimodal representation of cellular state by integrating transcriptomic profiles with inferred protein features; second, it employs a conditional diffusion model to generate perturbation-specific changes. Our approach introduces a Virtual Multimodal Cell State, which augments RNA-based representations with protein-level context, and a Mechanism-aware Drug-Gene Template, which consolidates multi-source biological knowledge for accurate drug representation. Generation is driven by a latent-space diffusion Transformer, regularized through quality-aware triplet constraints, including positive drug-protein pairs or protein-drug mismatched pairs, and explicit protein-reliability weighting. Extensive evaluation demonstrates that StateXDiff consistently enhances generalization performance across three challenging settings: unseen cell lines, unseen drugs, and combinatorial perturbations.