Head and neck squamous cell cancer (HNSCC) is an aggressive cancer resulting from heterogeneous causes. To reveal the underlying drivers and signaling mechanisms of different HNSCC tumors, we developed a novel Bayesian framework to identify drivers of individual tumors and infer the states of driver proteins in cellular signaling system in HNSCC tumors. First, we systematically identify causal relationships between somatic genome alterations (SGAs) and differentially expressed genes (DEGs) for each TCGA HNSCC tumor using the tumor-specific causal inference (TCI) model. Then, we generalize the most statistically significant driver SGAs and their regulated DEGs in TCGA HNSCC cohort. Finally, we develop machine learning models that combine genomic and transcriptomic data to infer the protein functional activation states of driver SGAs in tumors, which enable us to represent a tumor in the space of cellular signaling systems. We discovered four mechanism-oriented subtypes of HNSCC, which show distinguished patterns of activation state of HNSCC driver proteins, and importantly, this subtyping is orthogonal to previously reported transcriptomic-based molecular subtyping of HNSCC. Further, our analysis revealed driver proteins that are likely involved in oncogenic processes induced by HPV infection, even though they are not perturbed by genomic alterations in HPV+ tumors.