The purpose of this review is to explore eight novel immune checkpoints (PD-L2, B7-H3, VISTA, BTLA, TIM-3, LAG-3, TIGIT and GITR) in head and neck squamous cell carcinoma (HNSCC), including their biological properties, therapeutic potential and the possibility of combining them with other immune checkpoints (ICs) or emerging biotechnological approaches such as nanomaterials, oncolytic viruses (OVs) and tumour vaccines, with the aim of providing new treatment directions for HNSCC. This evidence concerns the gene PDCD1LG2 and head and neck squamous cell carcinoma.