Translational Challenges and Strategies for Antibody Therapeutics in Glioblastoma.
6 affiliations
- 1The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
- 2The First Clinical Medical College, Wenzhou Medical University, Wenzhou 325000, China.
- 3National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou 325000, China.
- 4Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China.
- 5Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
- 6Zhejiang Key Laboratory of Research and Transformation for Major Neurosurgical Diseases, Hangzhou 310009, China.
Abstract
Glioblastoma (GBM) remains difficult to control. Monoclonal antibodies (mAbs) have transformed the treatment of several extracranial cancers, but they have not consistently improved survival in GBM. This narrative review examines the main biological and translational barriers to antibody-based therapy. It also evaluates strategies to overcome them. We reviewed preclinical, translational, and clinical evidence on antibody delivery, target stability, the tumor microenvironment, target discovery, and emerging antibody formats. Heterogeneous blood-brain and blood-tumor barriers produce uneven intratumoral exposure, especially at infiltrative margins. Spatial and temporal heterogeneity promotes antigen loss and treatment escape. Lymphocyte dysfunction, myeloid dominance, and suppressive vascular and metabolic programs further limit immune activity. Receptor-mediated transcytosis and focused ultrasound may improve delivery. Single-cell and spatial profiling, surfaceome and endocytome proteomics, longitudinal sampling, and causal inference may improve target selection. Depending on their design, antibody-drug conjugates (ADCs) can deliver cytotoxic payloads, whereas bispecific constructs can enable immune redirection, dual-target recognition, or receptor-mediated transport. However, clinical benefit remains limited by construct design, target accessibility, regional exposure, toxicity, and inadequate biomarker selection. Successful translation requires modality-specific alignment of exposure at the relevant site of action, target requirements, immune dependence, molecular design, and safety. Biomarker-guided patient selection, spatial pharmacokinetic and pharmacodynamic validation, and early evidence of clinical benefit are also essential.
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BibTeX
@article{zhou2026translational,
title = {{Translational Challenges and Strategies for Antibody Therapeutics in Glioblastoma.}},
author = {Yangyi Zhou and You Li and Yu Chen and Peiqi Zhao and Bowen Wang and Haoliang Zhu and Hangzhe Sun and Tianyun Zhang and Anke Zhang and Yuanbo Pan and Kankai Wang},
journal = {Current oncology (Toronto, Ont.)},
year = {2026},
month = oct,
doi = {10.3390/curroncol33100619},
url = {https://europepmc.org/article/MED/42930186},
note = {CC BY},
}
RIS
TY - JOUR
TI - Translational Challenges and Strategies for Antibody Therapeutics in Glioblastoma.
AU - Yangyi Zhou
AU - You Li
AU - Yu Chen
AU - Peiqi Zhao
AU - Bowen Wang
AU - Haoliang Zhu
AU - Hangzhe Sun
AU - Tianyun Zhang
AU - Anke Zhang
AU - Yuanbo Pan
AU - Kankai Wang
PY - 2026
DA - 2026/10/14
JO - Current oncology (Toronto, Ont.)
DO - 10.3390/curroncol33100619
UR - https://europepmc.org/article/MED/42930186
AB - Glioblastoma (GBM) remains difficult to control. Monoclonal antibodies (mAbs) have transformed the treatment of several extracranial cancers, but they have not consistently improved survival in GBM. This narrative review examines the main biological and translational barriers to antibody-based therapy. It also evaluates strategies to overcome them. We reviewed preclinical, translational, and clinical evidence on antibody delivery, target stability, the tumor microenvironment, target discovery, and emerging antibody formats. Heterogeneous blood-brain and blood-tumor barriers produce uneven intratumoral exposure, especially at infiltrative margins. Spatial and temporal heterogeneity promotes antigen loss and treatment escape. Lymphocyte dysfunction, myeloid dominance, and suppressive vascular and metabolic programs further limit immune activity. Receptor-mediated transcytosis and focused ultrasound may improve delivery. Single-cell and spatial profiling, surfaceome and endocytome proteomics, longitudinal sampling, and causal inference may improve target selection. Depending on their design, antibody-drug conjugates (ADCs) can deliver cytotoxic payloads, whereas bispecific constructs can enable immune redirection, dual-target recognition, or receptor-mediated transport. However, clinical benefit remains limited by construct design, target accessibility, regional exposure, toxicity, and inadequate biomarker selection. Successful translation requires modality-specific alignment of exposure at the relevant site of action, target requirements, immune dependence, molecular design, and safety. Biomarker-guided patient selection, spatial pharmacokinetic and pharmacodynamic validation, and early evidence of clinical benefit are also essential.
SN - 1198-0052
SN - 1718-7729
ER -