scATD: a high-throughput and interpretable framework for single-cell cancer drug resistance prediction and biomarker identification

Abstract Transfer learning has been widely applied to drug sensitivity prediction based on single-cell RNA sequencing, leveraging knowledge from large datasets of cancer cell lines or other sources to improve the prediction of drug responses. However, previous studies require model fine-tuning for different patient single-cell datasets, limiting their ability to meet the clinical need for high-throughput rapid prediction. In this research, we introduce single-cell Adaptive Transfer and Distillation model (scATD), a transfer learning framework leveraging large language models for high-throughput drug sensitivity prediction. Based on different large language models (scFoundation and Geneformer) and transfer strategies, scATD includes three distinct sub-models: scATD-sf, scATD-gf, and scATD-sf-dist. scATD-sf and scATD-gf employs an important bidirectional style transfer to enable predictions for new patients without model parameter training. Additionally, scATD-sf-dist uses knowledge distillation from large models to enhance prediction performance, improve efficiency, and reduce resource requirements. Benchmarking across more diverse datasets demonstrates scATD’s superior accuracy, generalization and efficiency. Besides, by rigorously selecting reference background samples for feature attribution algorithms, scATD also provides more meaningful insights into the relationship between gene expression and drug resistance mechanisms. Making scATD more interpretability for addressing critical challenges in precision oncology.