Zhu Binyu, Cai Ying, Zhou Lingli, Zhao Lei, Chen Jiameng, Shan Xiaoting, Sun Xujie, You Qian, Gong Xiang, Zhang Wen, Zhu Helen He, Zhang Pengcheng, Li Yaping
State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, China.
Nat Commun. 2025 Jan 15;16(1):687. doi: 10.1038/s41467-025-55904-z.
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.
癌症免疫疗法的疗效依赖于足够数量的功能性免疫细胞。三阴性乳腺癌缺乏足够的免疫细胞浸润，因此需要辅助疗法来启动抗肿瘤免疫。然而，考虑到诱导全身免疫毒性，疗效的改善并不令人满意。在此，我们制备了一种由肽 - 药物两亲物形成的载有阿贝西利的超分子肽水凝胶，用于三阴性乳腺癌的新辅助免疫治疗，其中两亲物是一种形成β - 折叠肽与1 - 环己基 - 2 -（5H - 咪唑并[5,1 - a]异吲哚 - 5 - 基）乙醇（NLG919，一种吲哚胺2,3 - 双加氧酶1抑制剂）的缀合物。该水凝胶可注射到肿瘤部位并保留至少一周，以实现阿贝西利和NLG919的持续释放。阿贝西利能够诱导癌细胞发生免疫原性细胞死亡，并增加细胞毒性T淋巴细胞分泌白细胞介素 - 2。阿贝西利会不利地上调吲哚胺2,3 - 双加氧酶1，其犬尿氨酸生成活性可被NLG919抑制。这种新辅助免疫疗法可减少肿瘤复发和肺转移，并延长动物的生存期。与游离阿贝西利相比，这种水凝胶为三阴性乳腺癌的新辅助免疫治疗提供了一个毒性更低的潜在平台。
