Disentangled Multi-Modal Learning of Histology and Transcriptomics for Cancer Characterization

Histopathology remains the gold standard for cancer diagnosis and prognosis. With the advent of transcriptome profiling, multi-modal learning combining transcriptomics with histology offers more comprehensive information. However, existing multi-modal approaches are challenged by intrinsic multi-modal heterogeneity, insufficient multi-scale integration, and reliance on paired data, restricting clinical applicability. To address these challenges, we propose a disentangled multi-modal framework with four contributions: 1) to mitigate multi-modal heterogeneity, we decompose WSIs and transcriptomes into tumor and microenvironment subspaces using a disentangled multi-modal fusion module, and introduce a confidence-guided gradient coordination strategy to balance subspace optimization; 2) to enhance multi-scale integration, we propose an inter-magnification gene-expression consistency strategy that aligns transcriptomic signals across WSI magnifications; 3) to reduce dependency on paired data, we propose a subspace knowledge distillation strategy enabling transcriptome-agnostic inference through a WSI-only student model; and 4) to improve inference efficiency, we propose an informative token aggregation module that suppresses WSI redundancy while preserving subspace semantics. Extensive experiments on cancer diagnosis, prognosis, and survival prediction demonstrate our superiority over state-of-the-art methods across multiple settings. Code is available at GitHub.