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

Yantao Liu; Yu Peng; Chen Song; Zongran Liu; Xiaolong Yang; Shuqing Bian; Xiaolin Xiao; Haishuang Li; Jing Wang; Ziwen Sun; Xiaodan Liu; Bao Yang; David J H Shih; Jianyuan Luo; Hui Liang; Qing Chang

doi:10.1093/neuonc/noaf123

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. Online ahead of print.

Authors

Yantao Liu^{1

2

3}, Yu Peng^{1

2

3}, Chen Song^{4

5}, Zongran Liu⁶, Xiaolong Yang⁶, Shuqing Bian⁷, Xiaolin Xiao¹, Haishuang Li¹, Jing Wang², Ziwen Sun^{1

2

3}, Xiaodan Liu^{1

3}, Bao Yang⁸, David J H Shih⁹, Jianyuan Luo^{4

10}, Hui Liang^{1

11}, Qing Chang^{2

3}

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.