Noxa induction regulated by IRFs in response to IFN‐γ is essential in tumor elimination

Interferon‐γ plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, the bases of IFN‐mediated effects on tumor elimination are largely unknown. Here, we showed that BH3 profiles in tumor cells are altered by IFNs in various cancer cells with up‐ or down‐regulation of pro‐ or anti‐death BH3 proteins, respectively. Particularly, IFNs signify Noxa induction in a p53‐independent manner. Inhibition of Noxa expression using shRNA in tumor cells leads to resistance to LPS‐mediated tumor elimination in mice. Also, Noxa induction by IFN‐γ is regulated positively by IRF1, 3 and 7, but negatively by IRF4. Ectopic expression of IRF1, 3, or 7 in Noxa‐wild type BMK resulted in cell death that is abrogated by IRF4, but not in Noxa‐deficient BMK cells. Together, the results demonstrate that IFN‐γ directly alters BH3 profiles like Noxa in tumor cells to determine tumor susceptibility for tumor cell elimination.