Yang Yifan, Yu Qiumin, Zhang Haoyu, Liu Yuchen, Wang Hexuan, Yang Ningyi, Shi Yulian, Zhang Wanli, Wu Zijie, Huang Shitong, Xie Wenbin, Duan Ran, Mao Qiuli, Shi Xupeiyao, Gao Zheng, Wang Xiaoning, Guo Hanlin, Chen Lingxiao, Han Yi, Li Ximing, Chen Liyuan, Tang Siqi, Fan Ying, Yao Wenbing, Tian Hong, Gao Xiangdong
Jiangsu Key Laboratory of Draggability of Biopharmaceuticals and State, Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, China.
Shenyang Institutes for Food and Drug Control, China.
J Control Release. 2025 Apr 10;380:256-268. doi: 10.1016/j.jconrel.2025.01.094. Epub 2025 Feb 6.
Tumor-specific T cells play a crucial role in tumor immunity. However, these cells are often scarce and functionally exhausted within the tumor microenvironment (TME), leading to the limited efficacy of immunotherapy in many cancer patients. In contrast, increasing evidence suggests that the TME is rich in "bystander" T cells (T), most of which are virus-specific and unrelated to the tumor. These T cells retain functional memory characteristics and the potential to kill tumor cells. To utilize T cells in the TME for tumor elimination, we designed an intracellular delivery system, ASCP, encoding a T epitope to redirect tumor cell antigen specificity toward pre-existing T cells, resulting in effective tumor inhibition in multiple preclinical models. The ASCP-antigen peptide strategy restores the antigenicity of tumor cells and induces epitope spreading of tumor antigens, thereby eliciting more diverse tumor-specific T cell responses. Remarkably, this strategy incorporates MHC-II epitopes containing unnatural amino acids (p-nitrophenylalanine, termed NiraTh), which stimulate CD4 T cell-mediated immunity and assist CD8 T cells in clearing tumors. Overall, the ASCP-mediated tumor antigen reprogramming strategy provides important insights for cancer immunotherapy in populations with a history of common viral infections.
肿瘤特异性T细胞在肿瘤免疫中发挥着关键作用。然而，这些细胞在肿瘤微环境（TME）中往往稀少且功能耗竭，导致免疫疗法在许多癌症患者中的疗效有限。相比之下，越来越多的证据表明，TME中富含“旁观者”T细胞（T细胞），其中大多数是病毒特异性的，与肿瘤无关。这些T细胞保留了功能性记忆特征和杀伤肿瘤细胞的潜力。为了利用TME中的T细胞来消除肿瘤，我们设计了一种细胞内递送系统ASCP，其编码一个T细胞表位，以将肿瘤细胞抗原特异性重定向至预先存在的T细胞，从而在多个临床前模型中实现有效的肿瘤抑制。ASCP-抗原肽策略恢复了肿瘤细胞的抗原性，并诱导肿瘤抗原的表位扩展，从而引发更多样化的肿瘤特异性T细胞反应。值得注意的是，该策略纳入了含有非天然氨基酸（对硝基苯丙氨酸，称为NiraTh）的MHC-II表位，其刺激CD4 T细胞介导的免疫并协助CD8 T细胞清除肿瘤。总体而言，ASCP介导的肿瘤抗原重编程策略为有常见病毒感染史人群的癌症免疫治疗提供了重要见解。
