A Transfer Learning Framework for Predicting and Interpreting Drug Responses via Single-Cell RNA-Seq Data

Abstract

Chemotherapy is a fundamental therapy in cancer treatment, yet its effectiveness is often undermined by drug resistance. Understanding the molecular mechanisms underlying drug response remains a major challenge due to tumor heterogeneity, complex cellular interactions, and limited access to clinical samples, which also hinder the performance and interpretability of existing predictive models. Meanwhile, single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for uncovering resistance mechanisms, but the systematic collection and utilization of scRNA-seq drug response data remain limited. In this study, we collected scRNA-seq drug response datasets from publicly available web sources and proposed a transfer learning–based framework to align bulk and single cell sequencing data. A shared encoder was designed to project both bulk and single-cell sequencing data into a unified latent space for drug response prediction, while a sparse decoder guided by prior biological knowledge enhanced interpretability by mapping latent features to predefined pathways. The proposed model achieved superior performance across five curated scRNA-seq datasets and yielded biologically meaningful insights through integrated gradient analysis. This work demonstrates the potential of deep learning to advance drug response prediction and underscores the value of scRNA-seq data in supporting related research.