Introduction: Several literature sources have suggested that subjects with head and neck squamous cell carcinoma (HNSCC) display significant abnormalities of immunocompetent cells and cytokine secretion. Serious side effects and only a limited success with traditional therapies in HNSCC dictate the need for newer therapies.

Areas covered: This article comprehensively reviews the immune system alterations in HNSCC and the rationale behind various experimental immunotherapies, aiming at keeping this disease under control. Relevant publications were identified through the PubMed database search. The ongoing clinical trials regarding experimental immunotherapy agents in HNSCC were accessed at www.clinicaltrials.gov. The obtained information was thoroughly analyzed and systematized.

Expert opinion: Important and severe immune defects including T-cell dysfunction, cytokine alterations and antigen presentation defects are present in patients with HNSCC. In addition, tumor microenvironment was shown to play a critical role in the HNSCC progression. These discoveries have triggered a growing interest in immunotherapy as a potential treatment strategy for HNSCC. Effective immunotherapy could avoid the toxic side effects plaguing the current management of HNSCC. It is also hoped that immunotherapy will have long-lasting effects due to induction of immunologic memory. Promising directions include nonspecific immune stimulation, targeting specific HNSCC tumor antigens and therapeutic vaccines among others. These new agents may expand the existing therapy options for HNSCC in future.