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To investigate, we re\u2010evaluated divergent receptor\u2010biased IL\u20102 PEGylates (generated via site\u2010specific PEGylation at residues D20 (not\u2010\u03b2) and Y45 (not\u2010\u03b1)), alone or in combination. Results showed the not\u2010\u03b1 variant (Y45) activates regulatory T cells (Tregs) via \u03b2\u03b3 chain binding, overriding CD8+ T cells and impairing efficacy. Conversely, the not\u2010\u03b2 IL\u20102 (D20) is inert alone but spatially blocks Y45\u2019s \u03b2\u03b3 engagement, suppressing Treg activation. D20 also modulates activated CD8+ T cells by preferentially binding the \u03b1 chain, disrupting Y45\u2010mediated \u03b2\u03b3 signaling to prevent exhaustion and terminal differentiation. Synergy between these PEGylates highlights the \u03b1 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\u20102 strategies targeting \u03b1 chain regulation to optimize antitumor responses.<\/jats:p>","DOI":"10.1002\/advs.202414931","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T02:52:19Z","timestamp":1742439139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reshape the Fates of Treg and CD8+T Cells Through IL\u20102R\u03b1 by Synergizing Divergent Receptor\u2010Biased IL\u20102 PEGylates"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5931-0578","authenticated-orcid":false,"given":"Jiaqi","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University  Beijing 100191 China"},{"name":"Peking University Ningbo Institute of Marine Medicines  Ningbo Zhejiang 315832 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