Collectively, our results reveal a novel mechanism by which capsaicin sensitizes oral cancer cells to anticancer drugs through the up-regulation of autophagy and down-regulation of ribophorin II, and further indicate that the induction of necroptosis is a critical factor in the capsaicin-mediated chemosensitization of oral squamous carcinoma cells to conventional anticancer drugs. This evidence concerns the gene RPN2 and lip and oral cavity carcinoma.