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Anti-PD-L1 antibody-coated metal-organic framework for targeted PTPN2 Inhibitor delivery and enhanced immunotherapy of head and neck squamous cell carcinoma via cGAS-STING activation

Year: 2026
Type: article
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.
DOI: 10.1016/j.ijpx.2026.100694
Language: English
Open Access status: gold
Estimated APC paid: $2,590
OpenAlex ID: W7223004092
FWCI:
Cites: 35
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Related to: 10