Altogether, our studies support that HER3 may represent a key signaling hub in HNSCC, as the persistent tyrosine phosphorylation of HER3 underlies aberrant PI3K/mTOR signaling in HNSCC harboring wild type PIK3CA. In turn, HER3 blockade with CDX-3379 may exert its antitumor effects by suppressing the HER3-PI3K-AKT-mTOR tumor promoting circuity and reversing the immune suppressive TIME. The gene discussed is PIK3CA; the disease is head and neck squamous cell carcinoma.