Topology‐Aware Deep Learning on Higher‐Order Structures for Drug Response Prediction

ABSTRACT Accurate prediction of anticancer drug response remains a central challenge in precision oncology. Existing approaches often rely on pairwise modeling, overlooking higher‐order dependencies among drugs and cell lines. We present TopDr, a topology‐aware deep learning framework that encodes both drugs and cell lines as multiscale simplicial complexes, capturing interactions at the 0‐, 1‐, and 2‐simplex levels. By jointly integrating local higher‐order neighborhoods and global topological structures, TopDr generates enriched representations for sensitivity prediction. Across six benchmark datasets, TopDr consistently matches or surpasses state‐of‐the‐art baselines in both regression and classification tasks. Beyond predictive accuracy, TopDr offers mechanism‐level interpretability: attention over 1‐ and 2‐simplices highlights drug pairs and triplets with significant pathway enrichment, while cell line groupings reveal biologically coherent expression modules. These results demonstrate that modeling multiscale higher‐order topology yields predictions that are not only accurate and robust but also biologically interpretable, paving the way for more reliable drug response modeling.