RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity

Shivendra Singh, Jie Fang, Hongjian Jin, Lee-Ann Van De Velde, Andrew Cortes, Jiani Chen, Sivaraman Natarajan, Evon Poon, Qiong Wu, Christopher L. Morton, Mary A. Woolard, Waise Quarni, Jacob A. Steele, Jon P. Connelly, Liusheng He, Rebecca Thorne, Gregory Turner, Thomas Confer, Melissa Johnson, William V. Caufield, Burgess B. Freeman, Timothy Lockey, Andrew J. Murphy, Peter J. Murray, Takashi Owa, Shondra M. Pruett-Miller, Ruoning Wang, Louis Chesler, Julie R. Park, Andrew M. Davidoff, John Easton, Xiang Chen, Paul G. Thomas and Jun Yang ()
Additional contact information
Shivendra Singh: St. Jude Children’s Research Hospital
Jie Fang: St. Jude Children’s Research Hospital
Hongjian Jin: St. Jude Children’s Research Hospital
Lee-Ann Van De Velde: St. Jude Children’s Research Hospital
Andrew Cortes: St. Jude Children’s Research Hospital
Jiani Chen: St. Jude Children’s Research Hospital
Sivaraman Natarajan: St. Jude Children’s Research Hospital
Evon Poon: The Institute of Cancer Research
Qiong Wu: St. Jude Children’s Research Hospital
Christopher L. Morton: St. Jude Children’s Research Hospital
Mary A. Woolard: St. Jude Children’s Research Hospital
Waise Quarni: St. Jude Children’s Research Hospital
Jacob A. Steele: St. Jude Children’s Research Hospital
Jon P. Connelly: St. Jude Children’s Research Hospital
Liusheng He: St. Jude Children’s Research Hospital
Rebecca Thorne: St. Jude Children’s Research Hospital
Gregory Turner: St. Jude Children’s Research Hospital
Thomas Confer: St. Jude Children’s Research Hospital
Melissa Johnson: St. Jude Children’s Research Hospital
William V. Caufield: St. Jude Children’s Research Hospital
Burgess B. Freeman: St. Jude Children’s Research Hospital
Timothy Lockey: St. Jude Children’s Research Hospital
Andrew J. Murphy: St. Jude Children’s Research Hospital
Peter J. Murray: Max Planck Institute of Biochemistry
Takashi Owa: Eisai Inc.
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Ruoning Wang: The Ohio State University
Louis Chesler: The Institute of Cancer Research
Julie R. Park: St. Jude Children’s Research Hospital
Andrew M. Davidoff: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital
Xiang Chen: St. Jude Children’s Research Hospital
Paul G. Thomas: St. Jude Children’s Research Hospital
Jun Yang: St. Jude Children’s Research Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic and mesenchymal, which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown, and how to eradicate neuroblastoma regardless of its cell state is a clinical challenge. To better understand the cellular plasticity of neuroblastoma in chemoresistance, we define the transcriptomic and epigenetic map of adrenergic and mesenchymal types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We show that cancer cells not only undergo a bidirectional switch between adrenergic and mesenchymal states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. These cell state alterations are coupled with epigenetic reprogramming and dependency switching of cell state–specific transcription factors, epigenetic modifiers, and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances the anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

Date: 2025
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DOI: 10.1038/s41467-025-63979-x

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