Numerous studies have shown that the different isoforms vitamin E have distinct activity on carcinogenesis. α-Tocopherol (α-T), the most abundant vitamin E in certain types of food and animal tissues, has demonstrated a cancer-promoting effect in a number of human clinical trials and pre-clinical studies, whereas the γ- and δ- forms of Tocopherols and Tocotrienols have exhibited significant anticancer effect in various pre-clinical studies. However, the mechanisms underlying the tumorigenic effect of α-T have not yet been fully understood. In the present study, we found that α-T was able to activate Programmed death-ligand 1 (PD-L1)-mediated tumor-intrinsic signaling and immune suppression via JAK/STAT3-dependent transcriptional and ERK-dependent posttranscriptional mechanism. In line with PD-L1 induction, α-T treatment increased cancer cell viability in vitro and promoted tumor growth in LLC xenograft mouse model. The findings of the present study for the first time provided evidence that PD-L1-mediated tumor-intrinsic and immune escape mechanism contributed to the tumorigenic effect of α-T.