Interferon-signaling-defective cancer cells

Interferon-signaling-defective cancer cells are malignant cells that have lost the ability to respond to or produce Type I interferons (IFN-alpha/beta), a critical component of the innate immune response. This defect is frequently caused by loss-of-function mutations in the JAK-STAT signaling pathway, particularly in JAK1, JAK2, or STAT1, or through the downregulation of the IFNAR receptor (Zaretsky et al., 2016, NEJM). From a clinical perspective, these cells are significant because they often mediate primary or acquired resistance to immune checkpoint inhibitors, such as pembrolizumab, by failing to upregulate MHC class I and other T-cell attracting chemokines (Gao et al., 2016, Cell). However, this signaling deficiency renders the cells highly susceptible to oncolytic viruses, which exploit the lack of antiviral defenses to replicate selectively within the tumor (Stojdl et al., 2003, Cancer Cell). Therapeutic approaches targeting this phenotype include the use of engineered viruses like Talimogene laherparepvec (T-VEC) or the development of small molecules designed to bypass the signaling block. Monitoring for JAK/STAT mutations serves as a vital biomarker strategy for predicting immunotherapy failure and identifying candidates for viral-based interventions.

Other names

IFN-deficient cancer cellsIFN-unresponsive tumor cellsType I IFN signaling-deficient cellsJAK-STAT pathway-deficient cancer cells

Selective oncolysis via exploitation of impaired antiviral interferon signaling; induction of immunogenic cell death in cells unable to restrict viral replication.