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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI186034

Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models

Lizhi Pang,1 Songlin Guo,2 Yuyun Huang,1 Fatima Khan,1 Yang Liu,1 Fei Zhou,1 Justin D. Lathia,3 and Peiwen Chen1

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Pang, L. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Guo, S. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Huang, Y. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Khan, F. in: JCI | PubMed | Google Scholar |

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Liu, Y. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Zhou, F. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Lathia, J. in: JCI | PubMed | Google Scholar

1Department of Cancer Biology, Cleveland Clinic, Cleveland, United States of America

2Department of Neurological Surgery, Northwestern University, Chicago, United States of America

3Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, United States of America

Find articles by Chen, P. in: JCI | PubMed | Google Scholar

Published March 25, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186034.
Copyright © 2025, Pang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 25, 2025 - Version history
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Abstract

Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment (TME) and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3b-STAT3 pathway. Moreover, TAM-derived LGMN activated the integrin aV-AKT-P65 signaling to drive GBM cell proliferation and survival. Targeting LGMN-directed macrophage (inhibiting GSK3b and STAT3) and GBM cell (inhibiting integrin aV) mechanisms resulted in an anti-tumor effect in immunocompetent GBM mouse models that was further enhanced when combined with anti-PD1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN in promoting GBM progression and immunosuppression, providing effective therapeutic targets for improving immunotherapy in GBM.

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Version history
  • Version 1 (March 25, 2025): In-Press Preview
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