Interferon signaling and STING pathway in head and neck cancers: unlocking immune secrets and therapeutic frontiers

Head and neck squamous cell carcinomas (HNSCCs) rank seventh among the most prevalent malignancies globally. The immune response in cancer conditions governs the course of the disease and clinical outlook. Interferons (IFNs) are a key part of the innate immune system and are essential in modulating the tumor microenvironment (TME). Additionally, IFNs could influence proliferation and affect differentiation, emigration, and death of cancer cells. The cGAS-stimulator of interferon genes (STING) signaling identifies cytosolic DNA and triggers an immune response. Aberrant induction of the cGAS-STING signaling may lead to excess and sustained release of type-I IFN, leading to imbalanced aggregation in various tissues or organs. It is noteworthy that STING signaling has shown a dual role, both promoting tumor resistance and antitumor immunity. Moreover, STING agonists have been investigated in recent studies; however, challenges such as toxicity should be addressed. IFNs have also been used as monotherapy or adjuvant treatment before chemotherapy to increase efficacy against HNSCC tumors. The present review briefly describes IFN signaling with a focus on the STING pathway, and discusses its role in modulating immunotherapy and chemotherapy effects in HNSCC.