In a groundbreaking advance that heralds a new era in pediatric oncology, researchers at St. Jude Children’s Research Hospital have unveiled a promising therapeutic strategy to combat neuroblastoma, a devastating childhood cancer notorious for its complexity and resistance to treatment. Published in the prestigious journal Nature Communications, this study elucidates the intricate plasticity of neuroblastoma tumor cells and introduces an innovative treatment approach combining the molecular glue drug indisulam with immunotherapy to achieve unprecedented therapeutic success. This comprehensive research not only deciphers the elusive mechanisms underlying neuroblastoma heterogeneity but also provides a novel framework to circumvent tumor adaptability, forging a path toward more effective, long-lasting cures.
Neuroblastoma, a cancer originating in nerve tissue, typically arises from immature neural crest cells that fail to differentiate properly. This failure results in cells locked in a developmental limbo, endowing the tumor with remarkable plasticity — the ability to shift between distinct cellular states. These transitions between an adrenergic state, characterized by differentiated cells more susceptible to treatment, and a mesenchymal state, marked by less differentiated and therapy-resistant cells, have long perplexed oncologists. This dynamic plasticity enables tumor cells to evade therapies targeting a specific cellular identity, contributing to relapse and therapeutic failure. The newly published research exposes a yet underestimated degree of this plasticity, revealing that tumor cells can undergo multidirectional state transitions, exacerbating treatment challenges.
The team, led by Jun Yang, MD, PhD, from the Department of Surgery at St. Jude, focused their efforts on leveraging a unique class of compounds known as molecular glues. These small molecules exert their anti-cancer effects by binding specific target proteins and recruiting them to the cell’s degradation machinery, effectively “gluing” them together for destruction. Indisulam, a molecular glue drug, acts by targeting RBM39, an essential RNA splicing factor critical for neuroblastoma cell survival. By promoting the degradation of RBM39, indisulam disrupts RNA splicing processes, triggering cell death. Despite potent initial anti-tumor activity, prior models consistently encountered tumor relapse, indicating the presence of resistance mechanisms yet to be elucidated.
To dissect the resistive behavior, the researchers employed a triangulated approach, integrating genetic mouse models, patient-derived xenografts, and cell line-based systems. Surprisingly, each model exhibited distinct RNA sequencing profiles and patterns, a reflection of neuroblastoma’s profound heterogeneity. This variability hindered identification of a uniform therapeutic target and underscored the complexity of cellular states within tumors. However, leveraging sophisticated computational analyses projecting tumor profiles onto developmental trajectories, the team uncovered a remarkable phenomenon: neuroblastoma cells not only transit between adrenergic and mesenchymal states but also acquire novel traits during these shifts, suggesting an adaptive plasticity far more elaborate than previously recognized.
This revelation explained why monotherapies targeting single cell populations had limited efficacy. “Because tumors are a mixture of numerous subpopulations that can dynamically interconvert, targeting all of these simultaneously with drugs is not feasible due to toxicity concerns,” Dr. Yang noted. Instead, an alternative strategy was required—one that could neutralize tumor plasticity itself or exploit vulnerabilities shared across cellular states. Indisulam’s unique mode of action opened a new therapeutic window, but how to enhance its durability became the critical question.
Investigations revealed that treatment with indisulam triggered an innate immune response within the tumor microenvironment. Notably, the researchers observed recruitment of natural killer (NK) cells—potent immune effectors capable of direct tumor cell killing independent of prior sensitization. NK cells play a vital role in immune surveillance and are increasingly recognized as formidable adversaries against cancer cells. The induction of NK cell infiltration suggested that indisulam not only inhibits tumor intrinsic pathways but also activates an extrinsic anti-tumor immune mechanism.
Complementing these findings, the study detected upregulation of GD2, a glycosphingolipid abundantly expressed on neuroblastoma cells’ surfaces and a validated target for immunotherapy. GD2-targeted therapies, such as anti-GD2 monoclonal antibodies, have significantly improved outcomes in high-risk neuroblastoma by mediating antibody-dependent cellular cytotoxicity (ADCC). By combining indisulam with anti-GD2 antibodies, the researchers harnessed a dual mechanism: indisulam directly activated NK cells, enhancing their cytotoxic potential, while anti-GD2 antibodies flagged tumor cells for elimination through ADCC. This synergy translated into a “one-two knockout punch,” yielding complete tumor eradication in preclinical models regardless of the tumor’s cellular state.
This therapeutic breakthrough addresses a critical unmet need in neuroblastoma treatment. High-risk patients—who constitute nearly half of all cases—typically face aggressive therapies involving high-dose chemotherapy with substantial toxicity and relapse rates approaching 50%. Traditional treatment paradigms have struggled due to insufficient druggable targets and the tumor’s remarkable ability to evade single-targeted agents. The indisulam-immunotherapy combination circumvents this challenge by exploiting tumor biology and orchestrating an immune response that doesn’t rely solely on the tumor’s inherent molecular features, but rather leverages the immune system’s adaptable and potent cytotoxic arsenal.
The research team undertook extensive validation of this therapeutic approach across various experimental platforms. Beyond observing therapeutic efficacy, they conducted mechanistic studies illuminating the interplay between RNA splicing disruption, immune activation, and tumor plasticity. By uncovering the pleiotropic roles of indisulam—both as a molecular glue affecting key splicing factors and as an immunomodulatory agent—they have provided a conceptual advance that could reshape how molecular glues are perceived and employed in cancer therapy.
Beyond the immediate clinical implications for neuroblastoma, these findings carry broader significance for oncology. Tumor plasticity and heterogeneity represent formidable obstacles across multiple cancer types, undermining precision medicine efforts. This study exemplifies how combining targeted molecular degradation strategies with immune-based interventions can surmount these hurdles, highlighting a paradigm shift towards composite therapeutic regimens that address both intrinsic tumor cell biology and extrinsic tumor-immune system interactions.
Continuing this promising line of inquiry, the St. Jude team plans to further optimize the combination strategy and advance it toward clinical trials. Rigorous safety and efficacy assessments in human subjects will be paramount to translate these preclinical successes into viable treatments for children afflicted with neuroblastoma. Moreover, expanding understanding of molecular glue drugs’ immunomodulatory properties could unlock new avenues for their use across various malignancies characterized by dynamic cellular states and immune evasion.
The collaborative nature of this study, involving researchers from St. Jude, The Institute of Cancer Research in London, Max Planck Institute of Biochemistry, Eisai Inc., Nationwide Children’s Hospital, and The University of Tennessee Health Science Center, underscores the multidisciplinary effort required to unravel such complex biological phenomena. Funded by major grants from the American Cancer Society, the National Cancer Institute, and the American Lebanese Syrian Associated Charities (ALSAC), this comprehensive research initiative embodies a concerted push to confront and conquer childhood cancers.
In summary, this study conclusively demonstrates that tumor plasticity in neuroblastoma is more intricate and multidirectional than previously acknowledged, rendering traditional monotherapies inadequate. However, by harnessing the dual forces of indisulam-induced RNA splicing disruption and immune system activation—amplified through synergy with anti-GD2 immunotherapy—the researchers have devised a potent therapeutic approach able to thwart tumor adaptability and achieve complete responses in preclinical models. This advancement offers renewed hope for children battling neuroblastoma and opens a promising frontier for integrating molecular glue compounds within immune oncology paradigms.
Subject of Research: Neuroblastoma plasticity and therapeutic intervention combining molecular glues and immunotherapy
Article Title: ‘Molecular glue’ harnesses the power of the immune system to treat neuroblastoma
News Publication Date: September 17, 2025
Web References:
- St. Jude Neuroblastoma Information
- Jun Yang Lab at St. Jude
- St. Jude Research Departments
- St. Jude Homepage
- St. Jude Progress Magazine
- St. Jude Twitter
References:
Yang, J., Singh, S., Fang, J., Jin, H., Van de Velde, L.-A., Cortes, A., et al. (2025). Molecular glue-induced degradation of RBM39 combined with immunotherapy achieves complete responses in neuroblastoma. Nature Communications. https://doi.org/10.1038/s41467-025-63979-x
Image Credits: St. Jude Children’s Research Hospital
Keywords: Neuroblastoma, Immunotherapy, Molecular glue, Indisulam, Tumor plasticity, RNA splicing, Natural Killer cells, GD2, Antibody-dependent cellular cytotoxicity (ADCC), Pediatric cancer
