scTREAT: Latent Diffusion for Single-Cell Drug-Response Prediction

Generating drug-induced transcriptional responses requires a model to account for cellular background together with molecular identity and dose. We present scTREAT, the first diffusion framework to factorize state and drug guidance for single-cell drug-response prediction. A shared latent expression space connects baseline and response, while Guided Decomposable Attention (GD-Attn) injects a baseline representation and a dose-conditioned molecular embedding. Independent channel dropout exposes four conditioning states during training; inference combines three conditional predictions with separately specified state and drug coefficients, and dose modulates drug-guidance strength. On condition-level pseudobulk profiles derived from the Tahoe-100M single-cell atlas, scTREAT achieves the best value on 10 of 12 metrics for unseen cell line–drug combinations (UC) and 11 of 12 for unseen drugs (UD). Ablations examine condition injection, molecular representation, and guidance design. On UD, the relative gains over the second-best model reach 36.11% and 34.21% for DEG logFC-Spearman and logFC-Pearson. These results demonstrate the effectiveness of combining shared latent expression modeling with explicit state and drug conditioning for response prediction.