Introduction: Nasopharyngeal carcinoma (NPC) is a distinct head and neck squamous cell carcinoma in its etiological association of Epstein-Barr virus (EBV) infection, hidden anatomical location, remarkable racial and geographical distribution, and high incidence of locoregional recurrence or metastasis. Thanks to the advancements in proteomics in recent decades, more understanding of the disease etiology, carcinogenesis, and progression has been gained, potentially deciphering the molecular characteristics of the malignancy. Areas covered: In this review, we provide an overview of the proteomic aberrations that are likely involved or drive NPC development and progression, focusing on the contributions of major EBV-encoded factors, intercommunication with environment, protein features of high metastasis and therapy resistance, and protein-protein interactions that allow NPC cells to evade immune recognition and elimination. Finally, multistep carcinogenesis and subtypes of NPC from a proteomic perspective are inquired. Expert commentary: Proteomic studies have covered various aspects involved in NPC pathogenesis, yet much remains to be uncovered. Coherent study designs, optimal conditions for obtaining high-quality data, and compelling interpretation are critical in ensuring the emergence of good science out of NPC proteomics. NPC proteogenomics and proteoform analysis are two promising fields to promote the application of the proteomic findings from bench to bedside.
Keywords: Epstein–Barr virus; interactome; metastasis; multistep carcinogenesis; nasopharyngeal carcinoma; proteomics; secretome; therapy resistance.