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L.B and V.D acknowledge support from the Gates Foundation","award":["OPP1140482"],"award-info":[{"award-number":["OPP1140482"]}]},{"name":"Agency for Science Technology and Research (A*STAR) in Singapore"},{"name":"Agency for Science Technology and Research A*STAR NSS (PhD) graduate fellowship"},{"name":"AACR-Loxo Oncology Pediatric Cancer Research Fellowship"},{"name":"the China Scholarship Council","award":["201406380077"],"award-info":[{"award-number":["201406380077"]}]},{"name":"The CRI Irvington Postdoctoral Fellowship"},{"name":"International Postdoctoral Fellowship from the Swedish Research Council"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.12.744521","type":"posted-content","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T02:15:12Z","timestamp":1786673712000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting Tumor-derived Sphingosine Kinase 2 Unleashes Antitumor Immunity and Improves Survival of Mice with Group 3 Medulloblastoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0850-0328","authenticated-orcid":false,"given":"Sampurna","family":"Chatterjee","sequence":"first","affiliation":[{"name":"Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Immunology R&D, Translational Medicine & Bioinformatics, AstraZeneca, Boston, MA 02210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragya","family":"Kumar","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Tumor Microenvironment and Metastasis, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"},{"name":"Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwin S.","family":"Kumar","sequence":"additional","affiliation":[{"name":"Edwin L. 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Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Leman Biotech, Shenzhen, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5727-8992","authenticated-orcid":false,"given":"Meenal","family":"Datta","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Neurology at the Affiliated Hospital of Guangdong Medical University in Zhanjiang, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1272-8184","authenticated-orcid":false,"given":"William W.","family":"Ho","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Singapore Immunology Network (SIgN), Singapore 138648, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2758-8599","authenticated-orcid":false,"given":"Nilesh P.","family":"Talele","sequence":"additional","affiliation":[{"name":"Edwin L. 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Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Faculty of Advanced Techno-Surgery, Institute of Advanced Biomedical Engineering and Science, Tokyo Women\u2019s Medical University, Tokyo, 162-8666, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Landry","family":"Blanc","sequence":"additional","affiliation":[{"name":"Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, USA. 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