Our work has importantly demonstrated that EVs released by tumor cells do not necessarily recapitulate the complete protein profile of the originating cell, and hypothesize that EV protein cargo is determined by other factors that are advantageous for the tumor cell, such as growth, immune evasion, modification of the tumor microenvironment, cell-to-cell communication, drug resistance, etc. Finally, this work has identified several protein candidates for continued evaluation for HNSCC EV markers, including tenascin-C, HLA-A, E-cadherin, EGFR, EPHA2, and cytokeratin 19. Here, HLA-A is linked to head and neck squamous cell carcinoma.