Work

Targeted protein degradation via chimeric antigen receptor (CAR)-mediated antigen endocytosis in T cells

Year: 2026

Type: article

Abstract: Targeted protein degradation (TPD) relies on molecules engaging host protein degradation machinery. Here, we developed a novel TPD platform based on antigen endocytosis and degradation by chimeric antigen receptor (CAR) T cells. T cells expressing a CAR with TNFR1 as the antigen-binding domain (TNFR1T) were able to bind, endocytose, and degrade TNF in vitro. To enhance in vivo expansion and persistence of TNFR1T cells, BCOR and ZC3H12A were depleted, generating TNFR1T IF cells. In a human TNF transgenic mouse model of rheumatoid arthritis, a single infusion of TNFR1T IF cells sustainably reduced serum hTNF to near wild-type levels, leading to long-term disease remission. This approach extends CAR T cell targets from cells to extracellular proteins, enabling long-term degradation of inflammatory cytokines and durable remission in chronic inflammatory diseases.

Source: hLife

DOI: 10.1016/j.hlife.2026.05.003

Authors: Youguang Wang, Zihao He, Na Yin, Min Peng

Institutions: Peking University, Center for Life Sciences, State Key Laboratory of Molecular Oncology, Tsinghua University, Shanxi Medical University

Language: English

Topic: Protein Degradation and Inhibitors

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,300