Knowledge-driven multimodal mutual learning for cell line-targeted anticancer peptide prediction

As unique drugs positioned between small and macro molecules, anticancer peptides (ACPs) hold great potential in oncotherapy owing to their high selectivity and low toxicity. Nowadays, computational ACP prediction has emerged as a cost-effective alternative to bioassay screening, but most methods are limited to identifying bioactivity and fail to resolve tumor cell-specific targeting, primarily because of the sparse annotated data.

To fill this gap, we integrate a hybrid dataset compiled from five well-established peptide databases and propose TargetPC, a deep learning method tailored for cell line-targeted ACP prediction. TargetPC encodes multimodal representations of ACPs and cell lines via pretrained protein and omics models, and combines them via hierarchical intra- and inter-modal fusion for targeting prediction. This combination is further augmented by a mutual learning paradigm that distills domain knowledge from both ACP and cell line, enabling improved generalization under sparse supervision. Experimental results on the hybrid dataset demonstrate the effectiveness of TargetPC, which outperforms the state-of-the-art baselines in terms of prediction accuracy, and maintains strong generalization to unseen ACPs and cell lines. When extended to out-of-distribution samples, TargetPC has successfully screened dozens of novel ACPs targeted to breast cancer cells and uncovered biological motifs underlying its predictions. As a result, our TargetPC is expected to serve as a versatile tool for lead ACP discovery at a lower burden.

The source code and data are available at GitHub (https://github.com/liuxuan666/TargetPC).