Anti-PD-L1 antibody-coated metal-organic framework for targeted PTPN2 Inhibitor delivery and enhanced immunotherapy of head and neck squamous cell carcinoma
4 affiliations
- 1Department of Neurovascular Surgery, First Hospital of Jilin University, Changchun, Jilin, 130021, China
- 2Department of Thoracic Surgery II, Department of Lung Transplantation, Organ Transplantation Center, First Hospital of Jilin University, Changchun, Jilin, 130021, China
- 3Department of Clinical Laboratory, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China
- 4Department of Otolaryngology–Head and Neck Surgery, First Hospital of Jilin University, Changchun, Jilin, 130021, China; Corresponding author at: 1 Xinmin Street, Changchun, 130021, Jilin, China.
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a malignancy with limited responses to immune checkpoint blockade, due to insufficient tumor immunogenicity and immunosuppressive signaling. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) has emerged to negatively regulate antitumor immune responses. However, effective tumor-targeted delivery of PTPN2 inhibitors remains a major challenge. Herein, we developed an anti-PD-L1 antibody-functionalized Mn metal-organic framework nanoplatform (Pi@MOF@aP). The manganese-based MOF core efficiently encapsulated the PTPN2 inhibitor and enabled pH-responsive release under the acidic tumor microenvironment. Surface modification with anti-PD-L1 antibodies enhanced tumor targeting, promoted selective cellular uptake, and provided additional immune checkpoint blockade. Pi@MOF@aP exhibited potent cytotoxicity against HNSCC cells while maintaining favorable compatibility with normal oral keratinocytes. Mechanistically, Pi@MOF@aP-mediated PTPN2 inhibition activated the cGAS-STING pathway, increased cytokine production, and enhanced antitumor immune responses. In HNSCC mouse models, Pi@MOF@aP achieved efficient tumor accumulation, significantly inhibited tumor growth, prolonged survival, and promoted CD4 + and CD8 + T cells` infiltration with no obvious toxicity. Therefore, this study presents a multifunctional nanotherapeutic platform that integrates targeted PTPN2 inhibition, PD-L1 blockade, and cGAS-STING activation, providing a promising strategy for improving immunotherapy efficacy in HNSCC.
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BibTeX
@article{zhu2026antipdl1,
title = {{Anti-PD-L1 antibody-coated metal-organic framework for targeted PTPN2 Inhibitor delivery and enhanced immunotherapy of head and neck squamous cell carcinoma}},
author = {Zhanpeng Zhu and Rui Wang and Wei Li and Yu Cui},
journal = {International Journal of Pharmaceutics: X},
year = {2026},
month = oct,
doi = {10.1016/j.ijpx.2026.100694},
url = {https://doi.org/10.1016/j.ijpx.2026.100694},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Anti-PD-L1 antibody-coated metal-organic framework for targeted PTPN2 Inhibitor delivery and enhanced immunotherapy of head and neck squamous cell carcinoma
AU - Zhanpeng Zhu
AU - Rui Wang
AU - Wei Li
AU - Yu Cui
PY - 2026
DA - 2026/10/20
JO - International Journal of Pharmaceutics: X
DO - 10.1016/j.ijpx.2026.100694
UR - https://doi.org/10.1016/j.ijpx.2026.100694
AB - Head and neck squamous cell carcinoma (HNSCC) is a malignancy with limited responses to immune checkpoint blockade, due to insufficient tumor immunogenicity and immunosuppressive signaling. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) has emerged to negatively regulate antitumor immune responses. However, effective tumor-targeted delivery of PTPN2 inhibitors remains a major challenge. Herein, we developed an anti-PD-L1 antibody-functionalized Mn metal-organic framework nanoplatform (Pi@MOF@aP). The manganese-based MOF core efficiently encapsulated the PTPN2 inhibitor and enabled pH-responsive release under the acidic tumor microenvironment. Surface modification with anti-PD-L1 antibodies enhanced tumor targeting, promoted selective cellular uptake, and provided additional immune checkpoint blockade. Pi@MOF@aP exhibited potent cytotoxicity against HNSCC cells while maintaining favorable compatibility with normal oral keratinocytes. Mechanistically, Pi@MOF@aP-mediated PTPN2 inhibition activated the cGAS-STING pathway, increased cytokine production, and enhanced antitumor immune responses. In HNSCC mouse models, Pi@MOF@aP achieved efficient tumor accumulation, significantly inhibited tumor growth, prolonged survival, and promoted CD4 + and CD8 + T cells` infiltration with no obvious toxicity. Therefore, this study presents a multifunctional nanotherapeutic platform that integrates targeted PTPN2 inhibition, PD-L1 blockade, and cGAS-STING activation, providing a promising strategy for improving immunotherapy efficacy in HNSCC.
SN - 2590-1567
ER -