IL-27 protein is a member of the IL-6 superfamily, which is expressed on monocytes, endothelial cells, and dendritic cells. IL-27 protein is also referred to as the IL-12 p35-related protein, p28, is one subunit of a heterodimeric cytokine complex, and associates with another subunit EBI3 (EBV-induced gene 3), and IL-12 p40-related protein (IL-27B). IL-27 protein is an early product of activated antigen-presenting cells and drives the rapid clonal expansion of naive CD4(+) T cells and plays a role in the early regulation of Th1 cells initiation which drives efficient adaptive immune response. IL-27 protein has an antiproliferative activity on melanomas through WSX-1/STAT1 signaling. Thus, IL-27 protein may be an attractive candidate as an antitumor agent applicable to cancer immunotherapy.