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Beyond HLA-Ia: A multidimensional framework for Neoantigen immunotherapy

Liurui Ding1, Chenjing Guo1, Yehao Qin1

  • 1Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning 530004, China.

Cellular Immunology
|April 30, 2026
PubMed

Insights

This review proposes a genotype-agnostic immunotherapy framework for malignant gliomas. Strategies like HLA-E, γδ T cells, AI, and BBB delivery aim to overcome immune escape and improve treatment outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Biotechnology

Background:

  • Malignant gliomas, including glioblastoma (GBM), exhibit aggressive progression, high recurrence, and poor prognoses.
  • Current therapies offer limited survival benefits for glioma patients.
  • Existing neoantigen immunotherapies face significant hurdles in gliomas, such as HLA-Ia downregulation, tumor heterogeneity, immunosuppressive microenvironment, and the blood-brain barrier (BBB).

Purpose of the Study:

  • To review recent advances in overcoming immunotherapy barriers in gliomas.
  • To propose a multidimensional framework for developing broadly applicable neoantigen immunotherapies.
  • To establish a genotype-agnostic foundation for glioma treatment.

Main Methods:

  • Exploring HLA-E as an alternative antigen-presentation platform.
  • Investigating γδ T cells to bypass classical HLA-Ia dependence.
  • Utilizing artificial intelligence (AI) for neoantigen prioritization and optimization.
  • Examining emerging BBB-penetrating delivery technologies.

Main Results:

  • The proposed strategies aim to decouple neoantigen targeting from individual HLA restrictions.
  • This framework facilitates the development of "genotype-agnostic" immunotherapies.
  • The integrated approach enhances translational feasibility for glioma treatments.

Conclusions:

  • A multidimensional framework integrating novel strategies can overcome key barriers to effective glioma immunotherapy.
  • This approach holds promise for developing broadly applicable, off-the-shelf neoantigen immunotherapies.
  • The proposed framework offers new directions for overcoming immune escape in malignant gliomas.
Keywords:
Glioma immunotherapyHLA-EImmune escapeNon-classical HLA-Ibγδ T cells

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