High mobility group B1 (HMGB1) is a protein that is released from dying cancer cells in the context of immunogenic cell death (ICD). A recent study performed on patients with head and neck squamous cell carcinomas (HNSCC) reports that a chemoradiotherapy-induced increase in circulating HMGB1 levels predicts favorable outcome, echoing prior studies on neoadjuvant treatment of breast and rectal cancer in which the dynamics of HMGB1 plasma levels also have prognostic value. Hence, a therapy-induced rise in HMGB1 may be interpreted as a clinical sign of ICD and therapeutic response.