STE-DC2I Uncovers Driver Genes in Colorectal Cancer Subtypes Using Symbolic Trajectory-Embedded Dark Causal Inference.

Colorectal cancer (CRC) exhibits substantial molecular heterogeneity, necessitating the inference of subtype-specific driver genes and their interactions for drug-target discovery and precision oncology. Prior studies often fail to capture subtle, latent nonlinear regulatory mechanisms (dark causal relationships) driving tumor progression in specific subtypes. Here, we develop an explainable intelligence computational framework, Symbolic Trajectory-Embedded Dark Causal Interaction Inference (STE-DC2I), which combines symbolic trajectory embedding with historical prediction mechanisms to model nonmonotonic oscillatory dependencies between genes. Integrating single-cell transcriptomic and multiomics profiles from malignant epithelial subpopulations, STE-DC2I classifies CRC subtypes, reconstructs developmental trajectories, and uncovers interpretable subtype-specific driver genes with functional relevance. Unlike correlation-based and explicit causal approaches, STE-DC2I captures weak yet biologically critical regulatory signals, outperforming state-of-the-art methods in predicting subtype-specific CRC driver genes. Functional assays in CRC cell lines (in vitro) validated nine predicted driver genes, highlighting their therapeutic potential.This work systematically explores dark causal interactions between genes in CRC subtypes. STE-DC2I offers interpretable insights and a generalizable strategy for CRC drug-target discovery.