Targeting Tumor-derived Sphingosine Kinase 2 Unleashes Antitumor Immunity and Improves Survival of Mice with Group 3 Medulloblastoma.

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

Published in

bioRxiv : the preprint server for biology. Aug 13, 2026. Epub Aug 13, 2026.

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.
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.

PMID:
42845663
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.

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