WNT inhibition activates interferon stimulated gene expression by alleviating epigenetic repression of endogenous retroviruses.

As the use of immune checkpoint inhibitors for the treatment of cancer has expanded, convincing data have emerged correlating active WNT signaling with resistance to immunotherapies. To identify mechanisms through which WNT signaling limits anti-tumor immunity, we examined the response to WNT inhibition in a variety of human cancer cell lines that harbor distinct WNT pathway mutations. Our data show that inhibition of WNT signaling leads to activation of the TBK1/IRF3 dsRNA-sensing pathway and expression of interferon-stimulated genes (ISGs), independently of IFN/JAK/STAT signaling. Mechanistically, we show that WNT inhibition leads to increased chromatin accessibility at genomic loci harboring endogenous retroviruses (ERVs), resulting in ERV re-expression and activation of the dsRNA response. Increased ISG expression following WNT inhibition does not involve decreased MAP kinase signaling and therefore differs from reports documenting ISG induction in response to inhibition of other oncogenic pathways. Given the variety of tumor cell lines and WNT pathway mutations examined, these data suggest a mechanism by which WNT may drive immune evasion and several therapeutic avenues to reverse it, including tumor-targeted type 1 interferon stimulation and/or epigenetic therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-40894-9.