TMO-Net+: An Enhanced Tumor Multi-Omics Pre-Trained Network for Multi-Task Learning in Oncology.

BACKGROUND: Tumor heterogeneity arises from complex interactions among diverse biological factors, posing a major challenge for the development of robust multi-omics data integration methods. While the existing Tumor Multi-Omics pre-trained Network (TMO-Net) enables the fusion of multi-omics features into unified representations, its practical utility is constrained by issues such as missing modalities, incomplete within-omics data, and high-dimensional noise. To overcome these limitations, we propose TMO-Net+, an enhanced architecture specifically designed to improve the robustness and reliability of multi-omics modeling. METHODS: TMO-Net+ introduces several coordinated architectural enhancements. First, a feature attention encoder is applied to each omics data type to reduce the influence of modality-dependent input variation. Second, we combine a gated Mixture-of-Experts (MoE) module with a Product-of Experts (PoE) mechanism to capture sample-specific contributions and enable robust inference even when partial omics data are available. Additionally, a supervised deep classification head with a tailored loss function is incorporated to enhance the separability of learned embeddings in the latent space. RESULTS: Extensive experiments on pan-cancer datasets demonstrate that TMO-Net+ consistently outperforms the original TMO-Net, as measured by LogME scores. Furthermore, in various downstream tasks (e.g., pan-cancer classification, primary/metastatic site prediction, and prognostic modeling), TMO-Net+ achieves superior performance under partial-omics settings, which proves that it enhances the robustness and cross-cancer transferability of the multi-omics representations. CONCLUSIONS: The proposed TMO-Net+ improves the robustness and cross-cancer transferability of multi-omics representations within the evaluated TCGA cohorts. Biological interpretability analyses further show that TMO-Net+ prioritizes established cancer-driver genes, preserves cancer-dependent molecular-state information, and adaptively redistributes relative modality contributions across molecular states. By addressing modality-level missingness and modality-dependent input variation, it offers a reliable framework for integrative tumor analysis within the evaluated TCGA cohorts.