Innovative perspectives of immunotherapy in head and neck cancer. From relevant scientific rationale to effective clinical practice

•Comprehensive review about role of immune system in HNSCC.•Description of interplay between tumor immune infiltration and HPV status in HNSCC.•Immune escape mechanisms in HNSCC and clinical perspectives for the future.

It is now well established that head and neck cancer carcinogenesis is characterized by genetic instability and several immune defects, leading to unique host–tumor interactions. In such condition, recent improved comprehension and relevant findings could lead to identification of innovative molecular therapeutic targets, achieving considerable clinical and translational research. This review aims to summarize and to highlight most recent and relevant scientific rationale in this era of immunotherapy revival, and to correlate it to the near future clinical practice for the management of this challenging disease.