Transcriptional suppression of innate immunity by chimeric transcription factors

Immunosurveillance silencing by oncoproteins promotes tumor progression and immunotherapy evasion. However, little is known about the immunosuppression by chimeric transcription factors, drivers of many cancers such as alveolar rhabdomyosarcoma (aRMS). aRMS is an aggressive childhood soft tissue sarcoma mainly driven by the pathognomonic fusion oncoprotein PAX3–FOXO1 (or its variant PAX7–FOXO1). Chimeric transcription factors including PAX3/7-FOXO1 are notoriously difficult to target. Even with intensive chemotherapy and radiotherapy, the 5-year survival for the fusion-positive aRMS remains poor. No significant improvement has been made toward curing aRMS in decades, underscoring an urgent need to better understand the biology of PAX3/7-FOXO1 for developing more effective therapies. Our unpublished preliminary study indicates that PAX3-FOXO1 is involved in suppressing cancer cell-intrinsic immune response in aRMS cells. When the cancer cell-intrinsic immunosuppression is re-activated, potent anti-tumor activity is induced. These data led us to propose a novel hypothesis that PAX3/7–FOXO1 suppress the intrinsic innate immunity typified by type I interferon response through transcriptionally silencing cytosolic RNA and DNA sensing pathways, which can be leveraged to new immunotherapies. To test this hypothesis, we propose the following two Specific Aims: (1) To investigate the underlying mechanism of dsRNA sensing silenced by PAX3/7-FOXO1 (Aim 1); (2) To investigate the underlying mechanism of cytosolic DNA sensing silenced by PAX3/7–FOXO1 (Aim 2). This innovative study is to determine an unprecedent mechanism by which a chimeric transcription factor inhibits intrinsic type I interferon response by simultaneously suppressing the cytosolic RNA and DNA sensing pathways. The proposed research has translational relevance for children with high-risk aRMS as well as the potential to shed light on the molecular mechanisms of PAX3/7–FOXO1-driven aRMS and other cancers driven by chimeric transcription factors. Project Number: 1R01CA300571-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jun Yang | Institution: ST. JUDE CHILDREN'S RESEARCH HOSPITAL, MEMPHIS, TN | Award Amount: $617,486 | Activity Code: R01 | Study Section: Gene Regulation in Cancer Study Section[GRIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297270