To the best of our knowledge, this study represents the first comprehensive systematic review and network meta-analysis assessing the safety and efficacy of both first-line and second-line immunotherapies in patients with R/M HNSCC, including detailed evaluations of efficacy in subgroups with PD-L1 expression levels of ≥1% and ≥20%. This evidence concerns the gene CD274 and head and neck squamous cell carcinoma.