Transcriptional states define dependencies and therapeutic vulnerabilities in head and neck cancer

Here, we establish a mechanistic platform that converts transcriptomic diversity into drug-actionable tumor states. Integrating multi-cohort RNA-seq from 727 tumors across five independent datasets, genome-scale CRISPR dependency maps, and pharmacologic screening, we define distinct tumor survival circuits across HPV-negative HNSCC and nominate subtype-matched therapeutic strategies.

These circuits encompass a proliferative axis (MYC, MET/FAK, inflammatory and translational programs), an epithelial-differentiated/adhesion program, an EMT-like state with stromal activation, and mitochondrial/oxidative metabolic states, each mapping to selective liabilities (e.g., mitotic/autophagy control, ERBB/PI3K and cadherin signaling, OXPHOS/mitochondrial translation, and G2/M-integrin-Notch pathways, respectively).