Intratumoural vaccination via checkpoint degradation-coupled antigen presentation

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

doi:10.1038/s41586-025-09903-1

Intratumoural vaccination via checkpoint degradation-coupled antigen presentation

Nature. 2026 Jan 7. doi: 10.1038/s41586-025-09903-1. Online ahead of print.

Authors

Yu Han^#^{1

2

3}, Yicong Ma^#^{2

3}, Miao Pei^#¹, Shenyi Yin⁴, Jiahao Wang⁴, Liyu Guo¹, Yike Fang¹, Weiming Guo^{2

5}, Chunjiang Deng¹, Su Zhao¹, Xueyin Lu¹, Jianzhong Jeff Xi⁶, Heng Zhang⁷, Peng R Chen^{8

9

10

11}

Affiliations

¹ Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China.
² Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
³ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
⁴ Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China.
⁵ Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing, China.
⁶ Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing, China. jzxi@pku.edu.cn.
⁷ Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China. zhangheng@szbl.ac.cn.
⁸ Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, China. pengchen@pku.edu.cn.
⁹ Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. pengchen@pku.edu.cn.
¹⁰ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. pengchen@pku.edu.cn.
¹¹ Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing, China. pengchen@pku.edu.cn.

^# Contributed equally.

PMID: 41501465
DOI: 10.1038/s41586-025-09903-1

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 challenging^1-3. 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.