Ipilimumab, -omics, and head and neck cancers—update in 2025

Immunotherapy employing immune checkpoint inhibitors (ICIs) represents a pivotal approach for the management of recurrent and metastatic head and neck cancers (HNCs). Ipilimumab is a fully human monoclonal IgG1κ antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4), which can be introduced as a monotherapy or dual immunological regimen with nivolumab (anti-programmed death protein 1, PD-1). The background of the use of these monoclonal antibodies as combination immunotherapy is strongly associated with their different mechanisms of action. CTLA-4 and PD-1 are able to regulate the function of T cells through different mechanisms. Despite the better efficacy of immunotherapy with ipilimumab + nivolumab in HNCs observed in some cases, the overall effect regarding the comparison of ipilimumab <i>versus</i> ipilimumab + nivolumab is still unclear. The microbiome is one of the biomarkers that affect the response to immunotherapy with ICIs, including ipilimumab. Nevertheless, there is a clear lack of data in this context with regard to HNCs. The beneficial signature of the microbiome contributes to the prevention of the immune-related adverse events caused by ipilimumab. Notably, the incidence of gastrointestinal side effects induced by ICIs is significantly increased in the dual regimen with ipilimumab + nivolumab, which affects its recommendation for patients with HNCs.