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journal article·2025-05Open access

Reshape the Fates of Treg and CD8+T Cells Through IL‐2Rα by Synergizing Divergent Receptor‐Biased IL‐2 PEGylates

Jiaqi Sun, Lingfeng Guo, Dezhong Ji, Mengfan Yu, Boyang Cheng, Xingxing Zhu, Yeshuang Yuan, Siyu Wu, Yuanjie Zhang, Wen Shi, Zhiqian Chen, Xindang Chu, Jiayu Hu, Liwen Hua, Yiming Wang, Yanning Zhu, Yu Mu, Hanwen Sun, Chuanling Zhang, Qi Wang, Sulong Xiao, Lihe Zhang, Bo Zhang, Demin Zhou

Advanced Science· Volume 12· Issue 18
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Source abstract

Abstract

Abstract Clinical trials of receptor‐biased interleukin‐2 (IL‐2) variants in cancer therapy show limited efficacy. To investigate, we re‐evaluated divergent receptor‐biased IL‐2 PEGylates (generated via site‐specific PEGylation at residues D20 (not‐β) and Y45 (not‐α)), alone or in combination. Results showed the not‐α variant (Y45) activates regulatory T cells (Tregs) via βγ chain binding, overriding CD8+ T cells and impairing efficacy. Conversely, the not‐β IL‐2 (D20) is inert alone but spatially blocks Y45’s βγ engagement, suppressing Treg activation. D20 also modulates activated CD8+ T cells by preferentially binding the α chain, disrupting Y45‐mediated βγ signaling to prevent exhaustion and terminal differentiation. Synergy between these PEGylates highlights the α chain as a regulatory switch reshaping Treg, CD8+ T cell, and endothelial cell fates. In syngeneic tumor models, combined therapy enhanced CD8+ T cell infiltration, suppressed tumor growth, and reduced vascular leak syndrome risk. These findings propose combinatorial IL‐2 strategies targeting α chain regulation to optimize antitumor responses.
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Research context

OpenAlex topics: CAR-T cell therapy research · Immune Cell Function and Interaction · Cancer Immunotherapy and Biomarkers

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 China

Peking University Ningbo Institute of Marine Medicines Ningbo Zhejiang 315832 China

Department of Rheumatology Beijing Hospital National Center of Gerontology Institute of Geriatric Medicine Clinical Immunology Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China

First Clinical Division Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases Beijing 100081 China

Shenzhen Bay Laboratory Gaoke International Innovation Center Shenzhen Guangdong 518107 China

Dezhou University Dezhou Shandong 253023 China

State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Shandong Province

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