Advancing Cancer Prognosis with Hierarchical Fusion of Genomic, Proteomic and Pathology Imaging Data from a Systems Biology Perspective

Recent advances in multimodal learning have significantly improved cancer survival risk prediction. However, the joint prognostic potential of protein markers and histopathology images remains underexplored, largely due to the high cost and limited availability of protein expression profiling. To address this challenge, we propose HGP-Mamba, a Mamba-based multimodal framework that efficiently integrates histological with generated protein features for survival risk prediction. Specifically, we introduce a protein feature extractor (PFE) that leverages pretrained foundation models to derive high-throughput protein embeddings directly from Whole Slide Images (WSIs), enabling data-efficient incorporation of molecular information. Together with histology embeddings that capture morphological patterns, we further introduce the Local Interaction-aware Mamba (LiAM) for fine-grained feature interaction and the Global Interaction-enhanced Mamba (GiEM) to promote holistic modality fusion at the slide level, thus capture complex cross-modal dependencies. Experiments on four public cancer datasets demonstrate that HGP-Mamba achieves state-of-the-art performance while maintaining superior computational efficiency compared with existing methods. Our source code is publicly available at https://github.com/Daijing-ai/HGP-Mamba.git.

Multimodal survival prediction jointly analyzes histopathological whole-slide images (WSIs), genomic profiles, and clinical variables to stratify patients by risk. However, existing approaches often inadequately account for granularity differences across modalities, particularly in spatial organization and feature dimensionality. Within pathology, aggregating WSI patch features without preserving their spatial arrangement can obscure tissue architecture; across modalities, directly concatenating low-dimensional clinical variables with high-dimensional visual and genomic features may limit the contribution of clinical information to prediction. To address these challenges, we propose HGASurv, which introduces a hierarchical WSI encoding module and a clinical-guided graph propagation module for granularity-aware multimodal integration. The hierarchical WSI encoding module maps WSI patch features onto a spatial grid using their original coordinates and applies parallel convolutions to construct representations at patch, local-neighborhood, and regional scales. Genomic signature embeddings then query these scale-specific WSI representations through cross-modal co-attention, producing signature-conditioned morphological features. The clinical-guided graph propagation module uses clinical variables to define patient-similarity edges and propagates fused image-genomic node embeddings with graph attention, integrating clinical information through topology rather than feature concatenation. Across three TCGA cohorts, HGASurv achieved the strongest overall C-index performance, with ablation studies supporting the complementary contributions of the hierarchical WSI encoding and clinical-guided graph propagation modules. This design shows that matching representation and integration mechanisms to modality-specific granularity improves multimodal survival prediction.

We introduce ProtoPathway, an interpretable-by-design multimodal framework for cancer survival prediction that unifies whole slide imaging and transcriptomics through encoders producing biologically grounded representations on both sides of the fusion. On the histopathology side, $K$ learnable morphological prototypes, trained end-to-end with the survival objective, serve as the slide representation itself: patches flow into prototype tokens via soft assignment, compressing variable-length patch sets into fixed task-adaptive tokens. On the genomic side, a bipartite graph neural network encodes gene expression within the Reactome pathway hierarchy, producing pathway embeddings that reflect both constituent genes and their broader biological context through bidirectional message passing over a shared gene--pathway graph. Cross-modal attention then operates over a compact prototype $\times$ pathway matrix in which prototypes query pathways, modeling the biological direction in which molecular programs give rise to tissue morphology. Because both axes carry stable task-learned identity, the attention matrix is itself an interpretability output, yielding native inference-time attribution across the full biological hierarchy, from genes through pathways and prototypes to spatial tissue maps. We evaluate on five TCGA cancer cohorts, demonstrating competitive or superior survival prediction with substantially improved biological interpretability and reduced computational cost, with interpretability claims validated through fold-stratified rank-based population-level analysis. Our source code, model weights, and Reactome pathways, together with a unified codebase reimplementing all multimodal survival baselines under identical preprocessing and evaluation, are available at: https://github.com/AmayaGS/ProtoPathway.