XenoSignal: Investigating Intra- and Inter-Species Ligand-Receptor Interactions Using AlphaFold3

Xenograft models, in which human tumors are implanted into mouse hosts, offer a unique platform to study tumor-microenvironment (TME) interactions. Ligand-receptor (LR) interactions are central to intercellular communication in this context, but most inference tools rely on single-species databases and assume conserved function across orthologues. To test whether this assumption holds given sequence and structural divergence, we developed XenoSignal, a computational framework that integrates AlphaFold3 structural predictions to assess the plausibility of intraspecies and interspecies LR interactions. The pipeline predicts whether human-mouse orthologues retain or lose their functional interaction, enabling construction of a high-confidence cross-species LR resource. XenoSignal facilitates the interpretation of tumor-TME crosstalk in xenografts and prioritizes LR pairs for experimental validation. This resource enhances our ability to dissect interspecies signaling, uncover mechanisms of immune evasion, and identify candidate therapeutic targets in translational cancer models.