Zhao Yu, Song Donghui, Wang Zeyu, Huang Qingqing, Huang Fan, Ye Zhongfeng, Wich Douglas, Chen Mengting, Khirallah Jennifer, Gao Shuliang, Liu Yang, Xu Qiaobing
Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, China.
Nat Biomed Eng. 2025 Feb;9(2):234-248. doi: 10.1038/s41551-024-01285-5. Epub 2024 Nov 28.
The activation of cytotoxic T cells against tumour cells typically requires the cross-presentation, by antigen-presenting cells (and via major histocompatibility complex class I molecules), of an epitope derived from a tumour antigen. A critical step in antigen processing is the proteolysis of tumour antigens mediated by the ubiquitin-proteasome pathway. Here we describe a tumour vaccine leveraging targeted antigen degradation to augment antigen processing and cross-presentation. Analogous to proteolysis-targeting chimaeras, the vaccine consists of lymph-node-targeting lipid nanoparticles encapsulated with tumour antigens pre-conjugated with ligands that can bind to E3 ubiquitin ligases. In mice with subcutaneous human melanoma or triple-negative breast cancer, or with orthotopic mouse Lewis lung carcinoma or clinically inoperable mouse ovarian cancer, subcutaneously delivered vaccines prepared using tumour lysate proteins elicited antigen-specific adaptive immunity and immunological memory, and inhibited tumour growth, metastasis and recurrence, particularly when combined with immune checkpoint inhibition.
细胞毒性T细胞对肿瘤细胞的激活通常需要抗原呈递细胞通过主要组织相容性复合体I类分子对源自肿瘤抗原的表位进行交叉呈递。抗原加工的一个关键步骤是由泛素-蛋白酶体途径介导的肿瘤抗原的蛋白水解。在此，我们描述了一种利用靶向抗原降解来增强抗原加工和交叉呈递的肿瘤疫苗。类似于蛋白酶解靶向嵌合体，该疫苗由靶向淋巴结的脂质纳米颗粒组成，这些纳米颗粒包裹着与可结合E3泛素连接酶的配体预共轭的肿瘤抗原。在患有皮下人黑色素瘤或三阴性乳腺癌、原位小鼠Lewis肺癌或临床上无法手术的小鼠卵巢癌的小鼠中，使用肿瘤裂解物蛋白制备的皮下递送疫苗引发了抗原特异性适应性免疫和免疫记忆，并抑制了肿瘤生长、转移和复发，特别是与免疫检查点抑制联合使用时。
