Collectively, treatment-perturbation screens using targeted therapies such as mTOR inhibitors, EGFR inhibitors, glutamine inhibitors, and oHSV-1 have demonstrated the potential of synthetic-lethal approaches to treating HNSCC by mechanistically targeting mTOR signaling and cell-cycle regulation (INK128–palbociclib synergy), EGFR–PI3K pathway cross-talk (PIK3C2A-mediated TKI resistance), metabolic dependency on glutamine and ferroptosis regulators (GPX4), and epigenetic modulation of viral susceptibility via SUV39H2. This evidence concerns the gene PIK3C2A and head and neck squamous cell carcinoma.