Our finding that CD109-mediated increases in IL6Rα levels and STAT3 signaling leads to the stimulation of downstream IL-6 responses including stem cell marker expression and tumorigenicity, as well as NRF2 expression and activation of antioxidant enzymes, together with suppression of ROS levels, underscores a crucial role of CD109 in regulating IL-6-mediated cancer cell stemness, antioxidant status, and thus survival of SCC cells. This evidence concerns the gene NFE2L2 and cancer.