The suppressor of cytokine signaling 3 regulates glioma stem cell maintenance and immune microenvironment through signal transducer and activator of transcription 3 signaling
Abstract This study aims to elucidate the role of suppressor of cytokine signaling 3 (SOCS3) in glioma stem cells (GSCs) via single‐cell RNA sequencing (scRNA‐seq), focusing on its regulation of STAT3‐mediated self‐renewal, apoptosis resistance, and tumor microenvironment (TME) remodeling. ScRNA‐seq data from 19 high‐grade glioma patients were analyzed using Seurat, Harmony, and SingleR for clustering, annotation, and SOCS3 stratification (SOCS3‐High: n = 4; SOCS3‐Low: n = 15). Differential gene analysis, pathway enrichment, and CellChat were employed for TME characterization. In vitro, SOCS3‐overexpressing/silenced GSC11 models were tested via MTT, TUNEL, neurosphere assays, and STAT3 pathway modulation (IL‐6). In vivo, intracranial xenografts in nude mice evaluated tumor growth and survival. SOCS3 was downregulated in GSCs and neurons. SOCS3‐Low GSCs exhibited 777 differentially expressed genes enriched in T‐cell receptor, p53, and JAK‐STAT axis, suppressed T‐cell/microglia infiltration, and promoted oligodendrocyte precursor cell/astrocyte survival. SOCS3 overexpression reduced GSC proliferation, induced apoptosis, inhibited neurosphere formation, and suppressed STAT3 phosphorylation and stemness markers (OCT4/SOX2/NANOG). IL‐6 reactivated STAT3, reversing SOCS3‐mediated tumor suppression. In vivo, SOCS3 overexpression attenuated tumor growth and prolonged survival, counteracted by IL‐6. Low SOCS3 expression contributes to glioma progression by promoting STAT3 activation and an immunosuppressive TME. Targeting the SOCS3‐STAT3 axis may offer therapeutic potential.