ISG15 and cancer: Since Stat1 plays a key role in mediating the immune responses activated by the interferon signaling pathway through the transcriptional regulation of several interferon related genes including Irf7, Isg15, Oas2, Gbp3—all of which are upregulated by the SAM + 25(OH)D (Fig. 5c), we next tested the hypothesis that upregulation of Stat1 in part mediates the enhanced anti-cancer effect seen by the combination treatment.