Constitutive expression of the transcriptional co-activator IκBζ promotes melanoma growth and immunotherapy resistance.

IκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ's function in solid cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppresses Cxcl9, Cxcl10, and Ccl5 expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8(+) T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses.