2. Academic Validation
  3. Radiotherapy-derived engineered stem cell exosomes improve anti-glioma immunotherapy by promoting the formation of tertiary lymphoid structure and improve the release of type I interferon

Radiotherapy-derived engineered stem cell exosomes improve anti-glioma immunotherapy by promoting the formation of tertiary lymphoid structure and improve the release of type I interferon

  • J Nanobiotechnology. 2025 Mar 22;23(1):239. doi: 10.1186/s12951-025-03301-5.
Man Li # 1 2,  Lisen Lu # 3,  Qiuhong Bao # 4,  Minghui Zhou 1,  Bin Nie 2,  Yanchao Liu 1,  Kai Shu 1,  Ting Lei 1,  Mingxin Zhu 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 2 Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 3 College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China.
  • 4 Department of Oncology Medicine, Tiantai People's Hospital of Zhejiang Province, Tiantai, 317200, Zhejiang Province, China.
  • 5 Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. mxzhu@tjh.tjmu.edu.cn.
  • # Contributed equally.
PMID: 40121481 DOI: 10.1186/s12951-025-03301-5
Abstract

The absence of signaling pathways related to intrinsic immune activation in tumor cells and the immunosuppressive microenvironment limit lymphocyte infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study investigates strategies to activate intrinsic immune pathways in glioma cells, reverse immunosuppression, and induce tertiary lymphoid structures (TLS) within the glioma microenvironment (GME) to enhance natural and adaptive immune responses. We successfully induced antigen-presenting cell activation, macrophage/microglia polarization, and TLS formation in GME by intracranial delivery of BafA1@Rexo-SC, which comprises exosomes from irradiated bone marrow-derived stem cells overexpressing CD47 nanobodies and STING, loaded with the Autophagy Inhibitor BafA1. These exosomes efficiently activated the cGAS-STING pathway, leading to the formation of "lymphoid tissue organizer cells (Lto)" cells, VEGFA release for high endothelial microvessel formation, and chemokine release for T and B cell recruitment. BafA1@Rexo-SC also promoted macrophage phagocytosis of tumor cells and enhanced effector T cell function by blocking CD47, while releasing type I interferon. Our findings suggest novel therapeutic approaches for glioma treatment.

Keywords

Exosomes; Glioma; Stem cells; Tertiary lymphoid structures; Tumor microenvironment; cGAS-STING.

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