2. Academic Validation
  3. Tumor-associated macrophage-derived exosomes modulate the immunotherapeutic sensitivity of SHH-medulloblastoma by targeting m6A-modified FOXD1

Tumor-associated macrophage-derived exosomes modulate the immunotherapeutic sensitivity of SHH-medulloblastoma by targeting m6A-modified FOXD1

  • Neuro Oncol. 2025 May 22:noaf123. doi: 10.1093/neuonc/noaf123.
Yantao Liu 1 2 3,  Yu Peng 1 2 3,  Chen Song 4 5,  Zongran Liu 6,  Xiaolong Yang 6,  Shuqing Bian 7,  Xiaolin Xiao 1,  Haishuang Li 1,  Jing Wang 2,  Ziwen Sun 1 2 3,  Xiaodan Liu 1 3,  Bao Yang 8,  David J H Shih 9,  Jianyuan Luo 4 10,  Hui Liang 1 11,  Qing Chang 2 3
Affiliations

Affiliations

  • 1 Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China.
  • 2 Department of Neuropathology，Beijing Neurosurgical Institute, Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • 3 Beijing Key Laboratory of Research and Transformation of Biomarkers for Neurodegenerative Diseases, Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China.
  • 4 Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, 100191, China.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 6 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China.
  • 7 School of Information, Renmin University of China, Beijing, 100872, P.R. China.
  • 8 Department of Neuro-surgery, Tiantan hospital, Capital University of Medical Science, Beijing, China.
  • 9 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 10 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, 100191, China.
  • 11 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
PMID: 40401803 DOI: 10.1093/neuonc/noaf123
Abstract

Background: Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Infiltration of tumor-associated macrophages (TAMs) and m6A modification of RNA are correlated with poor prognosis and tumor progression in the Sonic Hedgehog (SHH) subtype (SHH-MB). However, the relationship between TAMs infiltration in SHH-MB and m6A modification status during tumor progression remains unclear.

Methods: Expression of m6A modification-related proteins was assessed in 40 cases of SHH-MB. Genes affected by TAM-derived exosomes were identified with methylated RNA immunoprecipitation Sequencing. Mechanisms of m6A modification of FOXD1 were evaluated and combinatorial treatment with AAV2/9-shFOXD1 and PD-1 inhibitors was investigated in the NeuroD2:SmoA1 mouse model.

Results: TAMs infiltration led to decreased METTL14 expression, which was mediated by TAM-derived exosomes containing METTL14-specific MicroRNAs. In turn, this led to lower levels of m6A modifications. Through a screen, FOXD1 was identified as a critical downstream target of TAM-derived exosomes, and its expression level was correlated with poor prognosis in SHH-MBs. Importantly, knockdown of FOXD1 in SHH-MB cells significantly promoted the release of chemokines CXCL10/11, resulting in CD8+ T cell recruitment. Furthermore, treatment with AAV2/9-shFOXD1 significantly enhanced the antitumor effect of the PD-1 inhibitor in transgenic SHH-MB mice.

Conclusion: Our study revealed for the first time that TAM-derived exosomes modulate m6A levels in SHH-MB, which promotes tumor progression via FOXD1. We identified FOXD1 as a novel therapeutic target whose inhibition sensitizes SHH-MB to immune checkpoint blockade.

Keywords

FOXD1; Immunotherapy; Medulloblastoma; TAMs; m6A.

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