Abstract
"Viral mimicry" refers to the induction of an innate immune response and interferon signaling by endogenous stimuli such as double-stranded RNA (dsRNA). This response has been shown to have strong cancer therapeutic potential, including by enhancing the effectiveness of immune checkpoint inhibition (ICI) therapies, and may represent a tumor suppression mechanism that needs to be overcome for malignant transformation to proceed. In a recent study, Zhou and colleagues identify KRAS, a frequently mutated oncogene, as a negative regulator of dsRNA and viral mimicry in an ICI-resistant colorectal cancer model. Oncogenic KRAS(G12D) mutations downregulate the RNA-binding protein DDX60 by activating the AKT signaling pathway, which inhibits STAT3, a critical transcription factor regulating DDX60 and other interferon-stimulated genes. Overexpression of DDX60, which competitively binds to dsRNA to prevent RISC-mediated degradation, or targeting of KRAS(G12D) elevated dsRNA levels, resulting in viral mimicry activation and potentiation of ICI treatment. These results establish KRAS as a promising target to sensitize immune "cold" tumors to ICI therapy and demonstrate the potential role of oncogenic mutations in viral mimicry evasion during tumorigenesis.