TNFR2-targeted nanoparticles for regulatory T-cell modulation in cancer immunotherapy: a narrative review
8 affiliations
- 1Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia
- 2Department of Hematology, School of Medical Sciences, Universiti Sains Malaysia
- 3UPMC Hillman Cancer Center, Division of Malignant Hematology and Medical Oncology, Department of Medicine, University of Pittsburgh School of Medicine
- 4Faculty of Chemical and Energy Engineering, Universiti Technology Malaysia
- 5School of Chemical Engineering, Universiti Sains Malaysia
- 6Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University
- 7Schmid College of Science and Technology, Chapman University
- 8School of Health and Biomedical Sciences, RMIT University
Abstract
Cancer immunotherapy has fundamentally transformed the therapeutic landscape of multiple malignancies, particularly through immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). However, the clinical efficacy of these agents remains limited in many patients due to primary or acquired resistance and treatment-associated immune-related adverse events (irAEs). Among emerging immunoregulatory targets, tumor necrosis factor receptor 2 (TNFR2) has attracted increasing attention owing to its preferential overexpression on highly suppressive intratumoral regulatory T cells (Tregs), which play a crucial role in immune evasion, therapeutic resistance, and unfavorable clinical outcomes across diverse malignancies. Although conventional TNFR2-targeting approaches, including monoclonal antibodies and small-molecule inhibitors, have demonstrated promising biological activity, their broader clinical translation is hindered by inadequate tumor penetration, systemic toxicity, off-target effects, and limited selectivity toward TNFR2+ immunosuppressive cell populations within the tumor microenvironment (TME). Nanoparticle-based delivery systems offer a promising platform to address these challenges by improving pharmacokinetic stability, enhancing tumor-selective accumulation, enabling TNFR2-targeting surface functionalization, and facilitating controlled payload release within the TME. In this narrative review, we summarize the molecular and immunological roles of TNFR2, examine the contribution of the TNFR2-Treg axis to tumor immune escape, and discuss current nanoparticle engineering strategies for TNFR2-directed therapy. We also evaluate emerging preclinical evidence, key translational challenges, and future perspectives for TNFR2-targeted nanomedicine in cancer immunotherapy.
Related
- Host Modulation Through Next-Generation Oral Probiotics: Can Targeted Microbiome Modulation Reverse the Inflammatory State in Periodontitis? A Narrative Review
- RPE-Targeted Laser Therapies for Central Serous Chorioretinopathy: Sublethal Modulation Versus Selective Injury and Repair—A Narrative Review
- Machine learning based regulatory T cells related gene signature for predicting the clinical outcome and immunotherapy benefits in skin cutaneous melanoma
- Correlation between circulating tumor cell levels and tumor response in patients with advanced hepatocellular carcinoma undergoing immunotherapy and molecular targeted therapy
- Cellular immunotherapy for lung cancer: current clinical evidence, translational challenges, and future perspectives: a narrative review
BibTeX
@article{akbar2026tnfr2targeted,
title = {{TNFR2-targeted nanoparticles for regulatory T-cell modulation in cancer immunotherapy: a narrative review}},
author = {Ali Akbar and Ali Mussa and Mohammad A. I. Al-Hatamleh and Lidawani Lambuk and Juhana Jaafar and Siti Nur Afifi Ahmad and JitKang Lim and Ma’mon M. Hatmal and Rosline Hassan and Vuk Uskoković and Magdalena Plebanski and Rohimah Mohamud},
journal = {Discover Oncology},
year = {2026},
month = jul,
doi = {10.1007/s12672-026-05486-z},
url = {https://doi.org/10.1007/s12672-026-05486-z},
note = {CC BY},
}
RIS
TY - JOUR
TI - TNFR2-targeted nanoparticles for regulatory T-cell modulation in cancer immunotherapy: a narrative review
AU - Ali Akbar
AU - Ali Mussa
AU - Mohammad A. I. Al-Hatamleh
AU - Lidawani Lambuk
AU - Juhana Jaafar
AU - Siti Nur Afifi Ahmad
AU - JitKang Lim
AU - Ma’mon M. Hatmal
AU - Rosline Hassan
AU - Vuk Uskoković
AU - Magdalena Plebanski
AU - Rohimah Mohamud
PY - 2026
DA - 2026/07/01
JO - Discover Oncology
DO - 10.1007/s12672-026-05486-z
UR - https://doi.org/10.1007/s12672-026-05486-z
AB - Cancer immunotherapy has fundamentally transformed the therapeutic landscape of multiple malignancies, particularly through immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). However, the clinical efficacy of these agents remains limited in many patients due to primary or acquired resistance and treatment-associated immune-related adverse events (irAEs). Among emerging immunoregulatory targets, tumor necrosis factor receptor 2 (TNFR2) has attracted increasing attention owing to its preferential overexpression on highly suppressive intratumoral regulatory T cells (Tregs), which play a crucial role in immune evasion, therapeutic resistance, and unfavorable clinical outcomes across diverse malignancies. Although conventional TNFR2-targeting approaches, including monoclonal antibodies and small-molecule inhibitors, have demonstrated promising biological activity, their broader clinical translation is hindered by inadequate tumor penetration, systemic toxicity, off-target effects, and limited selectivity toward TNFR2+ immunosuppressive cell populations within the tumor microenvironment (TME). Nanoparticle-based delivery systems offer a promising platform to address these challenges by improving pharmacokinetic stability, enhancing tumor-selective accumulation, enabling TNFR2-targeting surface functionalization, and facilitating controlled payload release within the TME. In this narrative review, we summarize the molecular and immunological roles of TNFR2, examine the contribution of the TNFR2-Treg axis to tumor immune escape, and discuss current nanoparticle engineering strategies for TNFR2-directed therapy. We also evaluate emerging preclinical evidence, key translational challenges, and future perspectives for TNFR2-targeted nanomedicine in cancer immunotherapy.
SN - 2730-6011
ER -