Taken together, the results reveal that VPS33B acts as a tumor suppressor in NPC, which is negatively regulated by nicotine and LMP-1 and interacts with NESG1 to co-regulate the EGFR/PI3K/AKT/c-Myc/P53/miR-133a-3p feedback loop signaling and its downstream cell cycle regulatory factors. Here, TP53 is linked to nasopharyngeal carcinoma.