Tumor Homing Nanoparticle Immunotherapy for Acute Clearance and Mitigation of T-cell Exhaustion in Humanized High-Risk Neuroblastoma
Year: 2026
Type: article
Abstract: Effective treatments for high-risk neuroblastoma, a pediatric malignancy with dismal survival outcomes, demand strategies that remodel the "cold" immunosuppressive tumor microenvironment (TME) to "hot" and proinflammatory. In this study, we interrogate the mechanistic efficacy of a pathogen-inspired nanoparticle (NP) technology that leverages the advantages of lipids to co-deliver a combination of physically distinct but functionally synergistic innate immune agonists for dual pathway activation in humanized mouse models. Specifically, our immunomodulatory NPs (immuno-NPs) co-deliver agonists of the stimulator of interferon (IFN) genes and Toll-like receptor 4 pathways. Together, dual pathway activation in target cells in the TME by immuno-NPs promotes the synergistic production of type I IFNs and other proinflammatory cytokines that powerfully remodel the cytokine milieu. We show that immuno-NPs can be delivered safely in the systemic blood circulation for deposition in the perivascular space of neuroblastoma primary tumors and metastases. Their broad uptake across immune cells, endothelial cells, and even tumor cells drives significant immune activation and restructuring of the cytokine milieu of the TME. We also demonstrate a pivotal role for otherwise exhausted CD8+ T cells that are local and already infiltrating the tumor. Immuno-NP-mediated rescue of this local T-cell subset is chiefly responsible for the acute clearance responses that may be essential for treatment efficacy in aggressive cancers like high-risk neuroblastoma. Taken together, our findings make a strong case for the use of pathogen-inspired, multi-innate pathway-activating therapies, such as immuno-NPs, for high-risk neuroblastoma and other solid tumor malignancies that urgently warrant effective TME remodeling approaches.
Source: Molecular Cancer Therapeutics
Authors: Griffin I. Kane, Miranda B. Diaz-Infante, Kim Wigglesworth, Ellis Lusi, Meghan Brassil, Esteban J. Rozen, Jamie Kady, Haruka Mori, John Lukas, Tiana Naylor, Ronnie W. Dinnell, Katherine C. Murphy, Christian Bernard B. Alarcon, Marcus Ruscetti, Michael Brehm, Jason M. Shohet, Prabhani U. Atukorale
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Alex's Lemonade Stand Foundation for Childhood Cancer, University of Massachusetts Amherst, National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, National Science Foundation Graduate Research Fellowship Program, Institute for Applied Life Sciences, University of Massachusetts Amherst
OpenAlex ID: W7140877905
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