Reshape the Fates of Treg and CD8+T Cells Through IL‐2Rα by Synergizing Divergent Receptor‐Biased IL‐2 PEGylates
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.
Authors
- Sulong Xiao (ORCID: https://orcid.org/0000-0002-6852-9504)
- Liwen Hua
- Xingxing Zhu (ORCID: https://orcid.org/0000-0002-5453-1769)
- Dezhong Ji (ORCID: https://orcid.org/0000-0003-0330-9882)
- Wen Shi (ORCID: https://orcid.org/0000-0002-6624-2331)
- Yanning Zhu (ORCID: https://orcid.org/0000-0001-8322-7742)
- Mengfan Yu (ORCID: https://orcid.org/0000-0003-3314-4695)
- Bo Zhang (ORCID: https://orcid.org/0000-0002-9652-1120)
- Yiming Wang (ORCID: https://orcid.org/0000-0001-7330-2235)
- Yeshuang Yuan
- Boyang Cheng
- Jiayu Hu (ORCID: https://orcid.org/0000-0003-2423-9465)
- Hanwen Sun (ORCID: https://orcid.org/0000-0002-3292-6276)
- Lihe Zhang (ORCID: https://orcid.org/0009-0009-6580-5743)
- Chuanling Zhang (ORCID: https://orcid.org/0000-0003-2910-3954)
- Siyu Wu (ORCID: https://orcid.org/0000-0002-9704-4557)
- Qi Wang (ORCID: https://orcid.org/0000-0002-1010-4298)
- Yuanjie Zhang
- Zhiqian Chen (ORCID: https://orcid.org/0000-0001-9537-8222)
- Demin Zhou (ORCID: https://orcid.org/0000-0003-0339-0959)
- Lingfeng Guo
- Jiaqi Sun (ORCID: https://orcid.org/0000-0002-5931-0578)
- Mu Yu (ORCID: https://orcid.org/0009-0002-0844-7686)
- Xindang Chu
Institutions
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Peking Union Medical College Hospital (CN)
- Shenzhen Bay Laboratory (CN)
- Dezhou University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-03-19
- DOI
- https://doi.org/10.1002/advs.202414931
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province