Oncofetal RNA-binding proteins of IGF2BP family suppress IRF-3 and NF-kB dependent transcription downstream of cytosolic RNA sensors

Activation of innate inflammatory signaling and tumor-specific antigen presentation in cancer cells provides a foundation for anti-cancer immunotherapies. Here, we show that Insulin-like Growth Factor 2 mRNA-Binding Proteins (IGF2BP1, IGF2BP2, and IGF2BP3), which are upregulated across various human malignancies, including acute myeloid leukemia (AML), suppress the activity of RNA-sensing pattern recognition receptors and downstream ISRE- and NF-κB-driven transcription. IGF2BPs exert a strong inhibitory effect on RIG-I signaling. This suppression is most pronounced when all three paralogs are co-expressed, particularly in embryonic-like hematoendothelial and leukemia stem cells. IGF2BPs suppress innate immune signaling via direct binding with TNFAIP3 mRNA and support of its RNA and protein expression. Genetic and pharmacological inhibition of IGF2BPs activates innate immune signaling and induces MHC class I gene expression in AML, highlighting a promising strategy for RIG-I- and TLR-based cancer immunotherapies.