Aside from several FDA-approved tissue agnostic precision medicines that may cover a small subset of HNSCC patients [i.e., infrequent NTRK1/2/3-rearrangments and ROS-1-rearrangement for larotrectinib and entrectinib, respectively], and an immune-hot subset of patients (~20–25% of patients) who respond to PD-1/PD-L1 inhibitors for reasons undefined, ~75–80% of HNSCC patients remain clinically inactionable by precision medicine. Here, CD274 is linked to head and neck squamous cell carcinoma.