Tumor-specific surface marker-independent targeting of tumors through nanotechnology and bioorthogonal glycochemistry

Hyesun Hyun; Bo Sun; Mostafa Yazdimamaghani; Albert Wielgus; Yue Wang; Stephanie Ann Montgomery; Tian Zhang; Jianjun Cheng; Jonathan S. Serody; Andrew Z. Wang

doi:10.1172/JCI184964

Tumor-specific surface marker-independent targeting of tumors through nanotechnology and bioorthogonal glycochemistry

Hyesun Hyun,¹ Bo Sun,² Mostafa Yazdimamaghani,¹ Albert Wielgus,¹ Yue Wang,³ Stephanie Ann Montgomery,¹ Tian Zhang,⁴ Jianjun Cheng,⁵ Jonathan S. Serody,¹ and Andrew Z. Wang⁶

Published March 11, 2025 - More info

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Abstract

Biological targeting is crucial for effective cancer treatment with reduced toxicity but is limited by the availability of tumor surface markers. To overcome this, we developed a nanoparticle-based, Tumor-specific suRfACE maRker-independent (TRACER) targeting approach. Utilizing the unique biodistribution properties of nanoparticles, we encapsulated Ac₄ManNAz to selectively label tumors with azide reactive groups. Surprisingly, while NP-delivered Ac₄ManNAz was cleared by the liver, it did not label macrophages, potentially reducing off-target effects. To exploit this tumor-specific labeling, we functionalized anti-4-1BB antibodies with dibenzocyclooctyne (DBCO) to target azide-labeled tumor cells and activate the immune response. In syngeneic B16F10 melanoma and orthotopic 4T1 breast cancer models, TRACER enhanced anti-4-1BB’s therapeutic efficacy, increasing median survival time. Immunofluorescence analyses revealed increased tumor infiltration of CD8⁺ T and NK cells with TRACER. Importantly, TRACER reduced hepatotoxicity associated with anti-4-1BB, resulting in normal serum ALT and AST levels and decreased CD8⁺ T cell infiltration in the liver. Quantitative analysis confirmed a 4.5-fold higher tumor-to-liver ratio of anti-4-1BB accumulation with TRACER compared to conventional anti-4-1BB antibodies. Our work provides a promising approach for developing targeted cancer therapies that circumvent limitations imposed by the paucity of tumor-specific markers, potentially improving efficacy and reducing off-target effects to overcome liver toxicity associated with anti-4-1BB.

Tumor-specific surface marker-independent targeting of tumors through nanotechnology and bioorthogonal glycochemistry

Hyesun Hyun,¹ Bo Sun,² Mostafa Yazdimamaghani,¹ Albert Wielgus,¹ Yue Wang,³ Stephanie Ann Montgomery,¹ Tian Zhang,⁴ Jianjun Cheng,⁵ Jonathan S. Serody,¹ and Andrew Z. Wang⁶

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Tumor-specific surface marker-independent targeting of tumors through nanotechnology and bioorthogonal glycochemistry

Hyesun Hyun,1 Bo Sun,2 Mostafa Yazdimamaghani,1 Albert Wielgus,1 Yue Wang,3 Stephanie Ann Montgomery,1 Tian Zhang,4 Jianjun Cheng,5 Jonathan S. Serody,1 and Andrew Z. Wang6

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Hyesun Hyun,¹ Bo Sun,² Mostafa Yazdimamaghani,¹ Albert Wielgus,¹ Yue Wang,³ Stephanie Ann Montgomery,¹ Tian Zhang,⁴ Jianjun Cheng,⁵ Jonathan S. Serody,¹ and Andrew Z. Wang⁶