Loss of the tumor suppressor PTEN activates cell-intrinsic interferon signaling to drive immune resistance.

ABSTRACT: Loss of the tumor suppressor PTEN is strongly associated with a lack of response to immune checkpoint blockade therapies in cancer patients, but the underlying mechanisms are not fully understood. We have developed a transformation model where knocking out PTEN in human mammary epithelial cells drives dependence on the p110β subunit of PI3K and, notably, elicits a robust induction of endogenous retroviral elements (ERVs) and activation of the interferon signaling. This constitutive cell-intrinsic interferon response, hallmarked by hyperactivated STAT1, is also observed in human tumors with a PTEN-low status. We further find that PTEN deficiency renders cancer cells resistant to the cytotoxic effects of immune cells and interferon-γ. Notably, PTEN loss also results in a dependency on an act

SUBMITTER: Wang Y 

PROVIDER: S-EPMC12458365 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature