Targeting Tumor-derived Sphingosine Kinase 2 Unleashes Antitumor Immunity and Improves Survival of Mice with Group 3 Medulloblastoma
Year: 2026
Type: preprint
Abstract: Group 3 medulloblastomas (G3MB) carry the worst prognosis among medulloblastoma subtypes, yet molecularly targeted therapies remain elusive. Standard treatments cause severe long-term morbidity in survivors. Here, we identify tumor-derived sphingosine kinase 2 (SPHK2) as an essential driver of G3MB initiation and progression. SPHK2 exacerbates local immunosuppression by suppressing cytotoxic T-cell and NK-cell activity while promoting regulatory T-cell infiltration. Genetic or pharmacologic SPHK2 inhibition using Opaganib attenuates pro-survival tumor signaling and restores anti-tumor immunity, significantly improving survival in syngeneic G3MB mouse models. Combining Opaganib with fractionated low-dose radiation (f-LDRT) further enhances antigen presentation and reprograms tumor-associated myeloid cells toward an anti-tumor phenotype. This combination therapy markedly prolongs survival without inducing significant toxicity. Overall, our study establishes SPHK2 as a previously unrecognized therapeutic target and presents a safe, effective, microenvironment-reprogramming regimen for G3MB. One Sentence Summary: Direct inhibition of tumor-derived SPHK2 overcomes local immunosuppression and downregulates pro-survival signaling in Group 3 medulloblastoma, while combination with fractionated low-dose radiation further enhances anti-tumor immunity and significantly improves survival.
Authors: Sampurna Chatterjee, Pragya Kumar, Ashwin S. Kumar, Pin-Ji Lei, Meenal Datta, Yuhui Zhao, William W. Ho, Nilesh P. Talele, Patrik Andersson, Mark Duquette, Shuji Kitahara, Landry Blanc, Samantha J. Wong, Wilhelmus J. Kwanten, David H. Ebb, Torunn I. Yock, Veronique Dartois, Dai Fukumura, Dan G. Duda, Lei Xu, Hye-Jung Kim, Rakesh K. Jain
Institutions: Massachusetts General Hospital, AstraZeneca (United States), University of South Florida, Moffitt Cancer Center, Agency for Science, Technology and Research, Harvard–MIT Division of Health Sciences and Technology, Bioprocessing Technology Institute, Massachusetts Institute of Technology, Leman Biotech Co., Ltd. (China), University of Notre Dame, Guangdong Medical College, Singapore Immunology Network, Tokyo Women's Medical University, Rutgers, The State University of New Jersey, Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Hackensack Meridian Health, Rutgers New Jersey Medical School, Université de Toulouse, Harvard University, University of Antwerp, Houston Methodist, Genentech, Dana-Farber Cancer Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Bill and Melinda Gates Foundation, Pediatric Cancer Research Foundation, Jane Coffin Childs Memorial Fund for Medical Research, American Brain Tumor Association, Massachusetts General Hospital, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Vetenskapsrådet, China Scholarship Council, National Institutes of Health, Ludwig Center at Harvard, Loxo Oncology, National Cancer Institute
Awards: G1402646273, G1423657041, G1449481090, G149958803, G1599094153, G2360436881, G2507465183, G3399638015, G4317237194, G4774430914, G5549562734, G7986362613, G8299328496, Reengineering obesity-induced abnormal microenvironment to improve PDAC treatment, Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism, G941982536
OpenAlex ID: W7202385129
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