With aim of blocking the crucial PD-L1 pro-metastatic mechanisms activated in the complex ecosystem of HNSCC, we have generated and characterized a novel anti-PD-L1 rFab’ and investigated its efficacy in reducing the aggressiveness of HNSCC in terms of cell viability, migration and invasion, as well as the signaling pathways involved. This evidence concerns the gene CD274 and head and neck squamous cell carcinoma.