Tumor cells with interferon pathway defects and related oncogenic alterations

This target refers to a specific oncogenic phenotype characterized by the loss or impairment of the Type I or Type II interferon (IFN) signaling pathways. In normal cells, IFN signaling triggers an antiviral state and promotes MHC expression; however, tumor cells often acquire defects in components like JAK1, JAK2, or STAT1 to evade immune detection (Zaretsky et al., NEJM 2016). These alterations are a double-edged sword: while they allow tumors to resist T-cell-mediated killing and checkpoint inhibitors, they also render the cells highly susceptible to oncolytic virus infections (Xia et al., Nature Communications 2016). Therapeutic strategies targeting this phenotype include the use of engineered viruses that selectively replicate in IFN-deficient environments, leading to direct oncolysis and the release of tumor antigens. Understanding these defects is critical for patient stratification in immunotherapy, as IFN pathway mutations are a primary driver of acquired resistance to PD-1/PD-L1 blockade (Gao et al., Cell 2016).

Other names

IFN-deficient tumor cellsInterferon signaling-deficient cancersIFN pathway-defective tumorsJAK/STAT deficient tumors

Oncolytic viruses selectively replicate in and lyse these cells due to impaired antiviral defenses (e.g., loss of PKR or MX1 induction). Conversely, these defects mediate resistance to immune checkpoint inhibitors by preventing interferon-gamma-induced MHC class I upregulation and T-cell recruitment (Zaretsky et al., NEJM 2016; Gao et al., Cell 2016).