Causal Cellular Context Transfer Learning (C3TL): An Efficient Architecture for Prediction of Unseen Perturbation Effects

Planning effective interventions in biological systems requires treatment-effect models that adapt to unseen biological contexts by identifying their specific underlying mechanisms. Yet single-cell perturbation datasets span only a handful of biological contexts, and existing methods cannot leverage new interventional evidence at inference time to adapt beyond their training data. To meta-learn a perturbation effect estimator, we present MapPFN, a prior-data fitted network (PFN) pre-trained on a synthetic biological prior with causal interventions, decoupling pre-training from limited wet-lab data. Unlike existing methods, MapPFN uses in-context learning to map a sequence of experiments to a post-perturbation distribution, enabling a single pre-trained model to adapt to new datasets and gene sets. Our results show that combining synthetic pre-training with fine-tuning on real single-cell data improves perturbation predictions across biological contexts. The code, model and data are available at https://marvinsxtr.github.io/MapPFN.

Single-cell perturbation prediction aims to infer how cells respond to unseen interventions and to achieve out-of-distribution (OOD) generalization, providing a computational route to understanding how perturbations reshape cellular programs over time. Existing machine learning methods have made important progress, but typically capture only one side of the response. Latent causal approaches seek mechanisms that support generalization and interpretation, yet often treat perturbation effects as static outcomes. Temporal models describe how gene expression changes across time, but usually do not explicitly recover the latent causal generative mechanisms driving these changes. In practice, perturbation effects are both latent and dynamical: interventions act through unobserved cellular programs, whose states evolve over time and give rise to observed expression profiles. Motivated by this view, we propose a latent dynamical causal generative model for single-cell perturbation data that jointly captures latent cellular programs, perturbation-conditioned mechanisms, and temporal evolution. We further provide an identifiability analysis showing that, under suitable conditions, the latent causal variables are recoverable up to standard equivalence classes. Guided by this analysis, we develop CITE-VAE, a learning framework for recovering latent cellular programs and their perturbation-driven dynamics from single-cell sequencing data. Experiments on Causal-3DIdent validate the theoretical results and the effectiveness of the proposed method in controlled settings. Additional experiments on real-world CRISPR-based single-cell perturbation data show improved generalization to unseen perturbations compared with state-of-the-art baselines, highlighting the practical robustness of our approach.

Predicting transcriptional responses to genetic perturbations is fundamental to functional genomics and therapeutic discovery. Recent deep learning models have shown promise in single-cell perturbation response prediction, but they typically generate each response in isolation, without explicitly leveraging related perturbations. We introduce PT-RAG (Perturbation-aware Two-stage Retrieval-Augmented Generation), a plug-in retrieval-and-conditioning module for generative cellular perturbation response. PT-RAG augments an existing perturbation-response backbone with learned access to related perturbation contexts. The key challenge is that relevance is not fixed in this setting: functionally related genes may elicit different effects across cell types. PT-RAG addresses this with a two-stage retrieval mechanism: GenePT-based semantic retrieval first identifies K candidate perturbations, after which a differentiable Gumbel-Softmax selector adaptively selects retrieved contexts conditioned on the control cell state, the query perturbation, and each candidate perturbation. We evaluate PT-RAG on two backbones, a STATE-style generator used as a frozen random reservoir and a fully trained scGPT, across cross-cell-type and cross-perturbation generalization tasks. PT-RAG consistently improves distributional similarity and often overall predictive quality; for example, on scGPT cross-cell-type results, the 2-Wasserstein distance drops by 5.9% relative to scGPT alone. The code to reproduce our experiments is available at https://github.com/difra100/PT-RAG_NIPS.