GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE347nnn/GSE347908/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE347908GEOGSEfalseEngineered receptor-biased IL-2–drug immunoconjugates selectively expand Tregs and suppress effector cells for autoimmune therapyAutoimmune and inflammatory diseases arise from a breakdown of immune tolerance driven by hyperactivation of effector lymphocytes and dysfunction of regulatory T (Treg) cells. Interleukin-2 (IL-2) supports both Treg maintenance and effector cells responses, necessitating careful dose optimization for selective immune regulation. Here, we report an immunoconjugate strategy that integrates Treg-selective cytokine signalling with localized pharmacological suppression by coupling a site-specifically PEGylated IL-2 variant (Y31-20K) to immunosuppressive small molecules. Through systematic screening, we identify Y31-20K-KU as the lead construct, which restores immune homeostasis in patient-derived lymphocytes and ameliorates pathology in mouse models of chronic colitis and collagen-induced arthritis. Mechanistically, Y31-20K-KU selectively expands Tregs while concurrently suppressing effector cells, and exhibited favourable safety with minimal immunogenicity, thereby overcoming limitations of cytokine- and small-molecule-based monotherapies. These findings establish IL-2–drug immunoconjugates as a clinically tractable strategy for bidirectional immune modulation, providing a versatile platform for reprogramming cytokine signalling in inflammatory diseases.2026/09/23GSE347908GSM10062670GSM10062671GSM10062662GSM10062663GSM10062664GSM10062665GSM10062666GSM10062667GSM10062668GSM1006266924676347908Homo sapiens