通过检查点降解偶联抗原呈递的瘤内疫苗接种，这一成果由深圳湾实验室陈鹏小组经过不懈努力而取得。2026年1月7日出版的《自然》杂志发表了这一最新研究成果。

在这里，该团队开发了一种瘤内疫苗嵌合体（iVAC），将肿瘤细胞重编程为抗原呈递状态（APC样肿瘤细胞），恢复抗肿瘤免疫。iVAC嵌合体由共价工程PD-L1降解物与免疫原性抗原结合组成，可以缓解免疫检查点抑制，同时加强外源抗原的交叉呈递。在功能上，iVAC诱导的抗原加工和呈递通过重新激活抗原特异性CD8⁺ T细胞，引发肿瘤的有效杀伤，同时重塑肿瘤微环境，促进持久的肿瘤特异性免疫。为了扩展这一策略，该课题组研究人员在体外、人源化小鼠模型和患者源性肿瘤模型中，用巨细胞病毒（CMV）衍生抗原对iVAC进行了主题化，以激活CMV特异性T细胞对抗乳腺癌。本研究为在肿瘤床内对癌细胞进行化学重编程以赋予APC样功能奠定了基础，为刺激抗肿瘤免疫提供了途径。

研究人员表示，抗原呈递细胞的交叉呈递减少导致肿瘤床内肿瘤反应性T细胞的稀缺，使得通过免疫原性重编程的原位T细胞再生非常理想，但具有挑战性。

附：英文原文

Title: Intratumoural vaccination via checkpoint degradation-coupled antigen presentation

Author: Han, Yu, Ma, Yicong, Pei, Miao, Yin, Shenyi, Wang, Jiahao, Guo, Liyu, Fang, Yike, Guo, Weiming, Deng, Chunjiang, Zhao, Su, Lu, Xueyin, Xi, Jianzhong Jeff, Zhang, Heng, Chen, Peng R.

Issue&Volume: 2026-01-07

Abstract: Decreased cross-presentation by antigen-presenting cells induces the scarcity of tumour-reactive T cells within the tumour bed, rendering in situ T cell rejuvenation through immunogenicity reprogramming highly desirable yet challenging1,2,3. Here we developed an intratumoural vaccination chimera (iVAC) to reprogram tumour cells into an antigen-presenting state (APC-like tumour cells) with restored anti-tumour immunity. The iVAC chimeras consist of a covalently engineered PD-L1 degrader conjugated to immunogenic antigens, which could relieve immune checkpoint inhibition while enforcing the cross-presentation of exogenous antigens. Functionally, the iVAC-induced antigen processing and presentation elicited potent tumour killing through reactivation of resident antigen-specific CD8+ T cells, which simultaneously remodelled the tumour microenvironment to promote durable tumour-specific immunity. Extending this strategy, we used iVAC with a cytomegalovirus (CMV)-derived antigen to activate CMV-specific T cells against breast cancer in vitro, in a humanized mouse model as well as in a patient-derived tumour model. This study establishes a foundation for chemically reprogramming cancer cells within tumour beds to endow APC-like functions, providing an avenue for stimulating anti-tumour immunity.

DOI: 10.1038/s41586-025-09903-1

Source: https://www.nature.com/articles/s41586-025-09903-1