Injectable supramolecular hydrogel co-loading abemaciclib/NLG919 for neoadjuvant immunotherapy of triple-negative breast cancer

Binyu Zhu, Ying Cai, Lingli Zhou, Lei Zhao, Jiameng Chen, Xiaoting Shan, Xujie Sun, Qian You, Xiang Gong, Wen Zhang, Helen He Zhu, Pengcheng Zhang () and Yaping Li ()
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Binyu Zhu: Chinese Academy of Sciences
Ying Cai: Chinese Academy of Sciences
Lingli Zhou: Nanjing University of Chinese Medicine
Lei Zhao: Zhengzhou University
Jiameng Chen: Chinese Academy of Sciences
Xiaoting Shan: Chinese Academy of Sciences
Xujie Sun: Chinese Academy of Sciences
Qian You: Shanghai Jiao Tong University
Xiang Gong: Chinese Academy of Sciences
Wen Zhang: Chinese Academy of Sciences
Helen He Zhu: Shanghai Jiao Tong University
Pengcheng Zhang: ShanghaiTech University
Yaping Li: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The efficacy of cancer immunotherapy relies on a sufficient amount of functional immune cells. Triple-negative breast cancer lacks enough immune cell infiltration, and adjuvant therapy is necessary to prime anti-tumor immunity. However, the improvement in efficacy is unsatisfactory with concern about inducing systemic immunotoxicity. Herein, we create an abemaciclib-loaded supramolecular peptide hydrogel formed by peptide-drug amphiphiles for neoadjuvant immunotherapy of triple-negative breast cancer, where the amphiphile is a conjugate of a β-sheet-forming peptide with 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol (NLG919), an inhibitor of indoleamine 2,3-dioxygenase 1. The hydrogel can be injected into the tumor site and retained for at least one week for the sustained release of both abemaciclib and NLG919. The abemaciclib is able to induce immunogenic cell death of cancer cells and increase interleukin-2 secretion by cytotoxic T lymphocytes. Abemaciclib adversely upregulates indoleamine 2,3-dioxygenase 1, whose kynurenine production activity is inhibited by NLG919. The neoadjuvant immunotherapy reduces tumor recurrence and pulmonary metastasis and prolongs the survival of animals. This hydrogel provides a potential platform for neoadjuvant immunotherapy of triple-negative breast cancer with reduced toxicity compared with free abemaciclib.

Date: 2025
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DOI: 10.1038/s41467-025-55904-z

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