The researchers initially encountered confounding results. “We used a genetic model, a patient-derived xenograft mouse model, and a cell line-based model, and all three models showed different RNA sequencing patterns,” Yang said. “We couldn’t find common features; every tumor had a unique pattern.”
By projecting these features onto the different stages of cell development, they determined that cells were undergoing unexpected multidirectional switches during development, notably switching from the mesenchymal to adrenergic cell state and vice versa. In some cases, theyeven acquired additional features, highlighting an unexpected depth to the plasticity of neuroblastoma cells.
“This data helped us understand the extent of heterogeneity in the tumors, and why developing a therapy is challenging; cells will simply switch to another state,” Yang explained. “Combining all the drugs to target each sub-cluster is not possible either, due to the toxicity. This is why the indisulam findings, when combined with immunotherapy, are remarkable.”
As part of the cell state switch triggered by indisulam, the researchers observed an innate immune response. They determined that a special type of immune cell called a natural killer cell is recruited to the tumor and that this immune response is at the center of indisulam’s mechanism.
The response was accompanied by an increase in GD2 expression, a protein that resides on the surface of cancer cells and is a key target for immunotherapy. They found that by supplementing indisulam treatment with anti-GD2 immunotherapy, the combination was a one-two knockout punch. “Indisulam can directly activate natural killer cells, and anti-GD2 exerts a mechanism called antibody-dependent cellular cytotoxicity,” Yang explained. “It’s two mechanisms that work together, the cellular toxicity and natural killer cells, to eradicate the tumor cell.” The therapeutic approach is being further developed for clinical testing.
Reference: Singh S, Fang J, Jin H, et al. RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity. Nat Commun. 2025;16(1):8287. doi: 10.1038/s41467-025-63979-x
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