AbstractMotivationDrug combination therapy shows significant advantages over monotherapy in cancer treatment. Since the combinational space is difficult to be traversed experimentally, identifying novel synergistic drug combinations based on computational methods has become a powerful tool for pre-screening. Among them, methods based on deep learning have far outperformed other methods. However, most deep learning-based methods are unstable and will give inconsistent predictions even by simply changing the input order of drugs. In addition, the insufficient experimental data of drug combination screening limits the generalization ability of existing models. These problems prevent the deep learning-based models from being in service.ResultsIn this article, we propose CGMS to address the above problems. CGMS models a drug combination and a cell line as a heterogeneous complete graph, and generates the whole-graph embedding to characterize their interaction by leveraging the heterogeneous graph attention network. Based on the whole-graph embedding, CGMS can make a stable, order-independent prediction. To enhance the generalization ability of CGMS, we apply the multi-task learning technique to train the model on drug synergy prediction task and drug sensitivity prediction task simultaneously. We compare CGMS’s generalization ability with six state-of-the-art methods on a public dataset, and CGMS significantly outperforms other methods in the leave-drug combination-out scenario, as well as in the leave-cell line-out and leave-drug-out scenarios. We further present the benefit of eliminating the order dependency and the discrimination power of whole-graph embeddings, interpret the rationality of the attention mechanism, and verify the contribution of multi-task learning.Availability and implementationThe code of CGMS is available viahttps://github.com/TOJSSE-iData/CGMS.